Immunology and Microbiology › Immunology

T-cell and B-cell Immunology

Works Count: 72086

Wikipedia

Description

This cluster of papers focuses on the development, function, and regulation of regulatory T cells (Tregs), particularly emphasizing the role of transcription factor Foxp3, TGF-ß induction, immune tolerance, thymic selection, memory T cells, IL-2 signaling, and their involvement in tumor immunity and immunological surveillance. The cluster also explores the implications of Tregs in autoimmunity and their potential for therapeutic interventions.

Keywords

Foxp3; TGF-ß; CD4+CD25+; Immune Tolerance; Autoimmunity; Thymic Selection; Memory T Cells; IL-2; Tumor Immunity; Immunological Surveillance

The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3

2001-01-01

Craig L. Bennett , Jacinda R. Christie , Fred Ramsdell +7 more

Help for cytotoxic-T-cell responses is mediated by CD40 signalling

1998-06-01

Sally R.M. Bennett , Federico Carbone , Freda Karamalis +3 more

CD4+CD25+ suppressor T cells: more questions than answers

2002-06-01

Ethan M. Shevach

CD4+CD25high Regulatory Cells in Human Peripheral Blood

2001-08-01

Clare Baecher‐Allan , Julia A. Brown , Gordon J. Freeman +1 more

Abstract Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD+CD25+ T cell regulatory population in their peripheral lymphoid … Abstract Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD+CD25+ T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4+ population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4+CD25+ regulatory cells isolated in mice. With TCR cross-linking, CD4+CD25high cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4+CD25− responder T cells in a contact-dependent manner. The CD4+CD25high regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RBlow on murine CD4+CD25+ regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4+CD25high regulatory cells and CD4+CD25− responder cells. Whereas higher ratios of CD4+CD25high T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.

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Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells

2010-01-31

Jung‐Hyun Park , Stanley Adoro , Terry I. Guinter +7 more

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T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions

1998-06-01

Stephen P. Schoenberger , René E. M. Toes , Ellen I. H. van der Voort +2 more

Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

1986-04-01

Timothy R. Mosmann , Holly Cherwinski , M W Bond +2 more

A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper … A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

T cell receptor antagonist peptides induce positive selection

1994-01-01

Kristin A. Hogquist , Stephen C. Jameson , William R. Heath +3 more

Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

2003-11-16

Susan M. Kaech , Joyce T. Tan , E. John Wherry +3 more

Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin

1986-11-01

Toshio Hirano , Kiyoshi Yasukawa , Hisashi Harada +7 more

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self

2005-03-22

Shimon Sakaguchi

T cell tolerance by clonal elimination in the thymus

1987-04-01

John W. Kappler , Neal W. Roehm , Philippa Marrack

Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

2009-05-22

Makoto Miyara , Yumiko Yoshioka , Akihiko Kitoh +7 more

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Lineage relationship and protective immunity of memory CD8 T cell subsets

2003-02-03

E. John Wherry , Volker Teichgräber , Todd C. Becker +5 more

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T-cell antigen receptor genes and T-cell recognition

1988-08-01

Mark M. Davis , Pamela J. Björkman

Reciprocal T H 17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid

2007-06-15

Daniel Mucida , Yunji Park , Gisen Kim +4 more

The cytokine transforming growth factor–β (TGF-β) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-β has also been found … The cytokine transforming growth factor–β (TGF-β) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-β has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T H 17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-β can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-β–dependent immune responses, capable of inhibiting the IL-6–driven induction of proinflammatory T H 17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.

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Lymphocyte Homing and Homeostasis

1996-04-05

Eugene C. Butcher , Louis J. Picker

The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte “homing” process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments … The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte “homing” process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments that control their differentiation and regulate their survival, and targets immune effector cells to sites of antigenic or microbial invasion. Recent advances reveal that the exquisite specificity of lymphocyte homing is determined by combinatorial “decision processes” involving multistep sequential engagement of adhesion and signaling receptors. These homing-related interactions are seamlessly integrated into the overall interaction of the lymphocyte with its environment and participate directly in the control of lymphocyte function, life-span, and population dynamics. In this article a review of the molecular basis of lymphocyte homing is presented, and mechanisms by which homing physiology regulates the homeostasis of immunologic resources are proposed.

B7/CD28 Costimulation Is Essential for the Homeostasis of the CD4+CD25+ Immunoregulatory T Cells that Control Autoimmune Diabetes

2000-04-01

Benoı̂t L. Salomon , Deborah J. Lenschow , Lesley Rhee +4 more

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CTLA-4 can function as a negative regulator of T cell activation

1994-08-01

Theresa L. Walunas , Deborah J. Lenschow , Christina Y. Bakker +5 more

Genetic and epigenetic fine mapping of causal autoimmune disease variants

2014-10-29

Kyle Kai-How Farh , Alexander Marson , Jiang Zhu +7 more

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Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection

1988-09-01

Austin L. Hughes , Masatoshi Nei

Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 Gene Encoding an ITIM Motif-Carrying Immunoreceptor

1999-08-01

Hiroyuki Nishimura , Masato Nose , Hiroshi Hiai +2 more

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CTLA-4 Control over Foxp3 + Regulatory T Cell Function

2008-10-10

Kajsa Wing , Yasushi Onishi , Paz Prieto-Martin +5 more

Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) … Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs-in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.

Counting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander Activation during Viral Infection

1998-02-01

Kaja Murali‐Krishna , John D. Altman , M. Suresh +5 more

Viral infections induce extensive T cell proliferation in vivo, but the specificity of the majority of the responding T cells has not been defined. To address this issue we used … Viral infections induce extensive T cell proliferation in vivo, but the specificity of the majority of the responding T cells has not been defined. To address this issue we used tetramers of MHC class I molecules containing viral peptides to directly visualize antigen-specific CD8 T cells during acute LCMV infection of mice. Based on tetramer binding and two sensitive assays measuring interferon-γ production at the single-cell level, we found that 50%–70% of the activated CD8 T cells were LCMV specific (2 × 107 virus-specific cells/spleen). Following viral clearance, antigen-specific CD8 T cell numbers dropped to 106 per spleen and were maintained at this level for the life of the mouse. Upon rechallenge with LCMV, there was rapid expansion of memory T cells, but after infection with the heterologous vaccinia virus there was no detectable change in the numbers of LCMV-specific memory CTL. Therefore, much of the CD8 T cell expansion seen during viral infection represents antigen-specific cells and warrants a revision of our current thinking on the size of the antiviral response.

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Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

1995-11-01

Elizabeth Tivol , Frank Borriello , Alain Schweitzer +3 more

Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1

1993-07-01

Jerry H. Brown , Theodore S. Jardetzky , Joan C. Gorga +4 more

Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue

2001-03-23

David Masopust , Vaiva Vezys , Amanda L. Marzo +1 more

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial … Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.

The Immunological Synapse: A Molecular Machine Controlling T Cell Activation

1999-07-09

Arash Grakoui , Shannon K. Bromley , Cenk Sumen +4 more

The specialized junction between a T lymphocyte and an antigen-presenting cell, the immunological synapse, consists of a central cluster of T cell receptors surrounded by a ring of adhesion molecules. … The specialized junction between a T lymphocyte and an antigen-presenting cell, the immunological synapse, consists of a central cluster of T cell receptors surrounded by a ring of adhesion molecules. Immunological synapse formation is now shown to be an active and dynamic mechanism that allows T cells to distinguish potential antigenic ligands. Initially, T cell receptor ligands were engaged in an outermost ring of the nascent synapse. Transport of these complexes into the central cluster was dependent on T cell receptor–ligand interaction kinetics. Finally, formation of a stable central cluster at the heart of the synapse was a determinative event for T cell proliferation.

Foxp3 programs the development and function of CD4+CD25+ regulatory T cells

2003-03-03

Jason D. Fontenot , Marc A. Gavin , Alexander Y. Rudensky

CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production

1998-07-20

Angela M. Thornton , Ethan M. Shevach

Peripheral tolerance may be maintained by a population of regulatory/suppressor T cells that prevent the activation of autoreactive T cells recognizing tissue-specific antigens. We have previously shown that CD4+CD25+ T … Peripheral tolerance may be maintained by a population of regulatory/suppressor T cells that prevent the activation of autoreactive T cells recognizing tissue-specific antigens. We have previously shown that CD4+CD25+ T cells represent a unique population of suppressor T cells that can prevent both the initiation of organ-specific autoimmune disease after day 3 thymectomy and the effector function of cloned autoantigen-specific CD4+ T cells. To analyze the mechanism of action of these cells, we established an in vitro model system that mimics the function of these cells in vivo. Purified CD4+CD25+ cells failed to proliferate after stimulation with interleukin (IL)-2 alone or stimulation through the T cell receptor (TCR). When cocultured with CD4+CD25- cells, the CD4+CD25+ cells markedly suppressed proliferation by specifically inhibiting the production of IL-2. The inhibition was not cytokine mediated, was dependent on cell contact between the regulatory cells and the responders, and required activation of the suppressors via the TCR. Inhibition could be overcome by the addition to the cultures of IL-2 or anti-CD28, suggesting that the CD4+CD25+ cells may function by blocking the delivery of a costimulatory signal. Induction of CD25 expression on CD25- T cells in vitro or in vivo did not result in the generation of suppressor activity. Collectively, these data support the concept that the CD4+CD25+ T cells in normal mice may represent a distinct lineage of "professional" suppressor cells.

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Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

2005-10-02

Laurie E. Harrington , Robin D. Hatton , Paul R. Mangan +4 more

PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

2009-12-14

Loise M. Francisco , Victor H. Salinas , Keturah Brown +4 more

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role … Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1−/− antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1−/−PD-L2−/− Rag−/− recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

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Structure of the human class I histocompatibility antigen, HLA-A2

1987-10-01

Pamela J. Björkman , Mark A. Saper , Boudjéma Samraoui +3 more

TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells

2006-02-01

Marc Veldhoen , Richard J. Hocking , Christopher J. Atkins +2 more

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Differential Expression of Chemokine Receptors and Chemotactic Responsiveness of Type 1 T Helper Cells (Th1s) and Th2s

1998-01-05

Raffaella Bonecchi , Giuseppe Bianchi , Paola Panina‐Bordignon +7 more

T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts … T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) chemokine receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding chemokines. The differential expression of chemokine receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coreceptors.

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Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

2003-12-15

WanJun Chen , Wenwen Jin , Neil J. Hardegen +5 more

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from … CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25- naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25- T cells into anergic/suppressor cells that are CD25+, CD45RB-/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs.

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Molecular mechanisms of T cell co-stimulation and co-inhibition

2013-03-08

Lieping Chen , Dallas B. Flies

Follicular Helper CD4 T Cells (TFH)

2011-03-02

Shane Crotty

T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of … T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of B cell help. T(FH) cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of T(FH) cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). T(FH) cells are important for the formation of germinal centers. Once germinal centers are formed, T(FH) cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers T(FH) differentiation, T(FH) functions, and human T(FH) cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg).

CD28/B7 SYSTEM OF T CELL COSTIMULATION

1996-04-01

Deborah J. Lenschow , Theresa L. Walunas , Jeffrey A. Bluestone

▪ Abstract T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second … ▪ Abstract T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional research that will unravel this important, yet complex, signaling pathway.

RAG-1-deficient mice have no mature B and T lymphocytes

1992-03-01

Peter Mombaerts , John Iacomini , Randall S. Johnson +3 more

Regulatory T Cells: Mechanisms of Differentiation and Function

2007-01-13

Steven Z. Josefowicz , Li‐Fan Lu , Alexander Y. Rudensky

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and … The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

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Regulatory T Cells and Immune Tolerance

2008-05-01

Shimon Sakaguchi , Tomoyuki Yamaguchi , Takashi Nomura +1 more

Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis

2004-04-05

Vissia Viglietta , Clare Baecher‐Allan , Howard L. Weiner +1 more

CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high … CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

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Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity

2014-03-21

Jason W. Griffith , Caroline L. Sokol , Andrew D. Luster

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that … Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein–coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.

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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

2006-04-30

Estelle Bettelli , Yijun Carrier , Wenda Gao +5 more

CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

1995-08-01

Matthew F. Krummel , James P. Allison

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface … The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

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Effector and memory T-cell differentiation: implications for vaccine development

2002-04-01

Susan M. Kaech , E. John Wherry , Rafi Ahmed

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Regulatory T Cells

2000-05-01

Shimon Sakaguchi

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MHC-Restricted Cytotoxic T Cells: Studies on the Biological Role of Polymorphic Major Transplantation Antigens Determining T-Cell Restriction-Specificity, Function, and Responsiveness

1979-01-01

R M Zinkernagel , Peter C. Doherty

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

1995-08-01

Shimon Sakaguchi , N Sakaguchi , M Asano +2 more

Abstract Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions … Abstract Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

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Perivascular Tertiary Lymphoid Structures in Autoimmune Disease

2025-06-24

Jörg J. Goronzy , Cornelia M. Weyand | Immunological Reviews

ABSTRACT Immunotherapy of autoimmune diseases has expanded substantially, yet autoimmunity remains incurable, and patients suffer from chronic destructive tissue inflammation that fails to resolve. Mechanisms underlying the endurance of autoimmune … ABSTRACT Immunotherapy of autoimmune diseases has expanded substantially, yet autoimmunity remains incurable, and patients suffer from chronic destructive tissue inflammation that fails to resolve. Mechanisms underlying the endurance of autoimmune memory and the lack of exhaustion are beginning to be understood. Here, we review emerging data on how decentralization of cellular immunity contributes to persistent autoimmune responses and chronicity of autoimmune tissue inflammation. Two processes are recognized as ensuring lasting immune memory: the generation of tissue‐resident memory T cells (TRM) and the formation of tertiary lymphoid structures (TLS). TLS, lymphoid aggregates formed outside of lymphoid organs, develop under conditions of chronic immune stimulation, such as autoimmune disease, anti‐tumor immunity, and during immune aging. TLS display heterogeneity in structure and cellular composition that may determine whether they ultimately serve as protective or pathogenic elements. Recent data have implicated TLS as a critical resource in upholding autoimmune responses, emphasizing their role in harming the host. In patients with autoimmune vasculitis, adventitial TLS drives protracted autoimmune disease by housing TCF1 hi CD4 + T stem cells that escape exhaustion and provide a continuous supply of pathogenic effector T cells to the disease lesions. The local production and stemness of CD4 + T cells bring resilience to autoreactive immunity, defining novel therapeutic targets in the management of autoimmune disease.

Thymic B cells in aging and autoimmune disease

2025-06-23

Sarah A. Wedemeyer , Ann V. Griffith | Frontiers in Immunology

Thymic B cells comprise a heterogenous population of cells localized primarily within the thymic medulla, a region populated by professional antigen-presenting cells (APCs) including dendritic cells, medullary thymic epithelial cells … Thymic B cells comprise a heterogenous population of cells localized primarily within the thymic medulla, a region populated by professional antigen-presenting cells (APCs) including dendritic cells, medullary thymic epithelial cells (mTECs), and macrophages. Through expression and presentation of self-antigens, these APCs are responsible for shaping the normal T cell repertoire by negatively selecting thymocytes recognizing self-antigens. It is now clear that thymic B cells have the capacity to participate in negative selection and present cognate antigens distinct from other medullary APCs, thus serving a non-redundant role in mediating T cell central tolerance. Recent work has linked thymic B cells with the development of multiple autoimmune diseases, many of which are increased in prevalence with aging. Here, we will provide a brief overview of the role of thymic B cell subsets in promoting negative selection and immune homeostasis, with a primary focus on the impact of aging on their tolerizing capacity and involvement in autoimmune diseases, highlighting thymic B cells as a potential novel therapeutic target to improve clinical outcomes in patients with autoimmune diseases.

Learning Human T Cell Behaviors through Generative AI Embeddings of T Cell Receptors

2025-06-22

Daniel Chen , Yapeng Su , James R. Heath | bioRxiv (Cold Spring Harbor Laboratory)

T cells interact with the world through T cell receptors (TCRs). The extent to which TCRs determine T cell behavior has not been comprehensively characterized. Our Tarpon model leverages advances … T cells interact with the world through T cell receptors (TCRs). The extent to which TCRs determine T cell behavior has not been comprehensively characterized. Our Tarpon model leverages advances in generative artificial intelligence to synthesize large-scale (>1M sequences) TCR atlases across human development and diseases into actionable insights. Tarpon creates: 1) bespoke sampling functions generating realistic Ag-specific TCRs, 2) embeddings revealing CD4+ and CD8+ single-positive TCR repertoires as distinct with divergent physiochemical properties, and 3) cross-dataset mappings of T cell states that validate fetal CD4+ versus CD8+ TCR differences in adults and find fetal type I innate T cells to map to MAIT and KIR+ adult CD8+ T cells which we verify via whole transcriptome analysis. Tarpon is a resource as a reference of TCRs across human physiological states and as a computational framework to create interpretable TCR embeddings, via physicochemical associations, that have broad implications for the field.

Resident memory T cell development is gradual and shows AP-1 gene expression in mature cells

2025-06-22

Neal P. Smith , Yu Yan , Youdong Pan +7 more | JCI Insight

Tissue-resident memory T (TRM) cells play a central role in immune responses across all barrier tissues after infection. However, the mechanisms that drive TRM differentiation and priming for their recall … Tissue-resident memory T (TRM) cells play a central role in immune responses across all barrier tissues after infection. However, the mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged newly generated and publicly available single-cell RNA-seq data generated across 10 developmental time points to define features of CD8+ TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture gene programs that increase their expression levels in T cells transitioning from an effector to a memory state. In addition to capturing tissue-specific gene programs, we defined a temporal TRM signature across skin and siIEL that can distinguish TRM from circulating T cell populations. This TRM signature highlights biology that is missed in published signatures that compared bulk TRM to naive or nontissue resident memory populations. This temporal TRM signature included the AP-1 transcription factor family members Fos, Fosb, Fosl2, and Junb. ATAC-seq analysis detected AP-1-specific motifs at open chromatin sites in mature TRM. Cyclic immunofluorescence (CyCIF) tissue imaging detected nuclear colocalization of AP-1 members in resting CD8+ TRM greater than 100 days after infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology.

Two distinct subpopulations of human stem-like memory T cells exhibit complementary roles in self-renewal and clonal longevity

2025-06-20

Danai Koftori , Charandeep Kaur , Laura Mora-Bitria +7 more | PLoS Biology

T stem cell-like memory cells (T SCM cells) are considered to be essential for the maintenance of immune memory. The T SCM population has been shown to have the key … T stem cell-like memory cells (T SCM cells) are considered to be essential for the maintenance of immune memory. The T SCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human T SCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo , different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi T SCM increases with age. Most importantly, CD95hi and CD95int T SCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int T SCM . While both T SCM subpopulations exhibit considerable multipotency, no single population of T SCM cells has both the properties of self-renewal and clonal longevity. Instead, the “stemness” of the T SCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int T SCM which have the property of clonal longevity and CD95hi T SCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.

Building a neural network model to define DNA sequence specificity in V(D)J recombination.

2025-06-20

Justin C. Harris , Jennifer N. Byrum , Cooper B. McKinney +4 more | PubMed

In developing lymphocytes, V(D)J recombination assembles functional antigen receptor (AgR) genes through rearrangement of the AgR loci to adjoin component gene segments. Each candidate gene segment for recombination is flanked … In developing lymphocytes, V(D)J recombination assembles functional antigen receptor (AgR) genes through rearrangement of the AgR loci to adjoin component gene segments. Each candidate gene segment for recombination is flanked by a recombination signal sequence (RSS), composed of heptamer and nonamer motifs separated by 12 or 23 base pairs. To initiate V(D)J recombination, the recombination activating proteins RAG1 and RAG2 create DNA double-stranded breaks between a 12/23-RSS pair and their adjoining gene segments. The basis for selection of individual RSSs during each V(D)J recombination event is not well understood due, in part, to the wide-spread distribution of the semi-conserved RSSs across the AgR loci. Using publicly-available data for V(D)J recombination efficiencies on randomized 12-RSSs, we first built a neural network model that delineates how changes in sequence at certain positions in the RSS affects recombination efficiency. Second, to interpret the model's decision-making process, we repurposed the game theoretic SHapley Additive exPlanations (SHAP) approach, with the results illustrating how nucleotides at pairwise positions in the heptamer provide synergistic contributions to recombination efficiency. Third, we trained a nonamer-informed neural network model with varied nonamer RSS substrates, and subsequently identified interdependent effects between the heptamer and nonamer regions on recombination efficiency.

T Cells Expressing Ras Homolog Family Member a Display Enhanced Cytotoxicity but are Reduced in Lupus Peripheral Blood

2025-06-19

Ziqi Xiong , Zhao Guan , Ainizati Hasimu +7 more | Immunological Investigations

This study aimed to explore the expression and clinical relevance of Ras homolog family member A (RhoA) in T cell subsets from patients with systemic lupus erythematosus (SLE). Peripheral blood … This study aimed to explore the expression and clinical relevance of Ras homolog family member A (RhoA) in T cell subsets from patients with systemic lupus erythematosus (SLE). Peripheral blood samples were obtained from newly diagnosed SLE patients and age- and sex-matched healthy controls. T cell subpopulations were analyzed by flow cytometry to quantify RhoA levels and associated cytotoxic markers, including granzyme B (GrB) and perforin (PFFN). Publicly available single-cell RNA sequencing (scRNA-seq) data were used to validate RhoA transcriptional patterns. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. RhoA was unevenly distributed among circulating T cell populations, with the highest protein expression observed in CD8+ and effector memory subsets. RhoA+ T cells showed significantly higher GrB and PFN levels compared to their RhoA+ counterparts. In early-stage SLE, RhoA expression in T cells was significantly reduced compared to healthy individuals. However, a greater proportion of CD8+RhoA+ cells expressed GZMB in SLE patients. ROC analysis yielded area under the curve (AUC) values of 0.6720 for CD4+RhoA+ and 0.6635 for CD8+RhoA+ T cells. RhoA+ T lymphocytes exhibit enhanced cytotoxic potential and may serve as early immunological markers for the identification of SLE.

Cold-blooded vertebrates evolved regulatory B cells to participate in inflammatory diseases

2025-06-19

Jie Wang , Wenjing Dong , Tiantian Tian +7 more | Cell Communication and Signaling

Regulatory B cell (Breg), known for its immunosuppressive properties through the provision of IL-10, plays a critical role in the control of inflammatory diseases. Although Breg has been discovered for … Regulatory B cell (Breg), known for its immunosuppressive properties through the provision of IL-10, plays a critical role in the control of inflammatory diseases. Although Breg has been discovered for over two decades in mammals, its existence in non-mammalian vertebrates remains unclear. Here, we aimed to explore the differentiation mechanism and functional profiles of teleost CD25L+ Breg to gain insights into the origin and evolution of Breg. Flow cytometry, RNA-seq, qPCR, morphological analysis, immunoblotting, immunofluorescence, recombinant IL-35 stimulation, cell co-culture in Transwell system were performed to reveal the phenotypic features, differentiation mechanism and suppressive functions of teleost CD25L+ Breg. To elucidate the immunoregulatory role of CD25L+ Breg in vivo, bacterial infection and inflammatory bowel disease (IBD) models were established in teleost fish. Systemic and local inflammatory responses were assessed by flow cytometry, immunofluorescence, histological analysis, and cytokine measurements. Phenotypically, we identified a unique IgM+CD25L+ B cell subset, termed CD25L+ B cells, characterized by their capacity to produce IL-10 and IL-12p35 in a cold-blooded vertebrate, the grass carp. Mechanistically, IL-35 stimulation induced the differentiation of CD25L- B cells into CD25L+ B cells, promoting the production of IL-35 and IL-10 via STAT3 activation. Functionally, teleost CD25L+ B cells served as a conventional Breg subtype that exerted its immunosuppressive functions on effector T cells and neutrophils via cell contact or cytokine delivery. Upon bacterial infection, CD25L+ Breg increased earlier than CD25L+ Treg and produced IL-10. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced IBD model, Breg frequency and IL-10 levels increased significantly during IBD remission, and Breg adoptive transfer could prevent IBD development and contribute to intestinal tissue repair. These novel findings reveal that fish have evolved Breg with specialized anti-inflammatory functions, providing evolutionary insights into the phylogenetic origin and functional conservation of Breg from fish to mammals.

Generation of antigen-specific and functionally stable Treg cells from effector/memory T cells for cell therapy of immunological diseases

2025-06-18

Norihisa Mikami , Ryoji Kawakami , Atsushi Sugimoto +2 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T cells (Tconvs) into Foxp3 + regulatory T cells (Tregs) that are as stably suppressive as naturally occurring Tregs … Abstract One strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T cells (Tconvs) into Foxp3 + regulatory T cells (Tregs) that are as stably suppressive as naturally occurring Tregs (nTregs). To achieve the conversion in vitro for mice and humans, we induced high Foxp3 expression in antigen- and IL-2-stimulated Tconvs by CDK8/19 inhibition, and established Treg-specific epigenetic changes by depriving CD28 co-stimulation during in vitro Treg induction to specifically promote the expression of Treg signature genes, especially Foxp3 . Repeating this process, with intermittent resting cultures containing IL-2 only, enabled in a short duration efficient conversion of naïve as well as effector/memory CD4 + Tconvs, including Th1, Th2 and Th17 cells, into Foxp3 + Tregs, which were similar to nTregs in transcription and epigenetic modification. Induced Tregs (iTregs) thus generated were indeed functionally and phenotypically stable in vivo and effectively suppressed inflammatory bowel disease and graft-versus-host disease in mouse models. Adoptive cell therapy with such effector/memory Tconv-derived, functionally stable, iTregs would be able to achieve antigen- and disease-specific treatment of immunological diseases. One Sentence Summary Antigen-specific and functionally stable Treg cells can be generated in vitro from effector/memory T cells for cell therapy of immunological diseases.

Clonal sharing of CD8+ T‐cells links skin and joint inflammation in psoriatic arthritis

2025-06-17

Lucy E. Durham , Frances Humby , Nora Ng +7 more | Arthritis & Rheumatology

Objective Psoriatic arthritis (PsA) is an HLA class I‐associated inflammatory arthritis that develops in up to 30% of people with psoriasis. We tested the hypothesis that skin and joint inflammation … Objective Psoriatic arthritis (PsA) is an HLA class I‐associated inflammatory arthritis that develops in up to 30% of people with psoriasis. We tested the hypothesis that skin and joint inflammation in PsA is linked in terms of CD8+ T‐cell phenotype and clonality. Methods Using scRNAseq (n=6 skin with n=5 paired synovial tissue and/or n=5 paired synovial fluid) and spatial transcriptomics (n=1 paired skin and synovial biopsies, n=4 unpaired biopsies), we compared the transcriptional signature, T‐cell receptor repertoire and cell neighbourhoods of T‐cells from skin and synovial tissue and/or fluid from patients with PsA. Results We identified an enrichment of type‐17 CD8+ tissue‐resident memory (T RM ) T‐cells in both skin and joint, with a stronger IL‐17 signature in the skin than the joint. CD8+ T RM cells resided in distinct cell neighbourhoods in skin and joint but were located adjacent to antigen‐presenting cells in both sites. Several T‐cell clones were shared between the skin and joint. Across the six patients, 155 CD8+ T‐cell clones were shared between the two sites, comprising 1,071 CD8+ T cells and taking up a median of 13% of the skin and 8% of the joint CD8+ TCR repertoire. CD8+ skin‐joint shared clones tended to have a similar phenotype at both sites, characterised by increased expression of genes associated with a cytotoxic, tissue‐resident phenotype. Conclusion Our findings support the hypothesis that skin and joint inflammation in PsA is linked in terms of CD8+ T‐cell clonality and that specific T‐cells migrate between these compartments to propagate inflammation across both sites.

Single-cell analysis of temporal immune cell dynamics in alopecia areata reveals a causal role for clonally expanded CD8+ T cells in disease

2025-06-17

Zhenpeng Dai , Yuqian Chang , Eunice Lee +5 more | Cell Reports

Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells

2025-06-16

Ken Oestreich , Srijana Pokhrel , Devin M Jones +7 more | bioRxiv (Cold Spring Harbor Laboratory)

CD8+ virtual memory T (TVM) cells are memory-like cells that rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM cells arise independently of foreign … CD8+ virtual memory T (TVM) cells are memory-like cells that rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM cells arise independently of foreign antigen encounter, the mechanisms governing their development are not fully understood. Here, we identify the transcription factor Aiolos as a negative regulator of TVM cells. We observed higher quantities of TVM cells in the spleens of uninfected Aiolos-deficient (Ikzf3-/-) mice relative to wild-type (WT). Furthermore, Ikzf3-/- TVM cells produced higher levels of IFN-γ and granzyme B. In addition, we found that Ikzf3-/- TVM cells accumulated to higher quantities in the lungs within 24 hours of influenza virus infection. In line with enhanced TVM functional capacity and lung trafficking, Aiolos-deficient mice cleared virus more rapidly and exhibited reduced morbidity relative to WT animals. Mechanistically, we observed that Aiolos represses the TVM transcriptional regulator Eomes and the IL-15R subunit CD122 (IL-15Rβ/IL-2Rβ), known contributors of TVM cell generation. Collectively, these findings establish Aiolos as a novel molecular repressor of TVM generation and function.

Autoimmune Diseases: Molecular Pathogenesis and Therapeutic Targets

2025-06-16

Xiaoshuang Song , Hantian Liang , Fang Nan +7 more | MedComm

ABSTRACT Autoimmune diseases are a set of disorders in which the immune system attacks one's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. Affecting approximately 10% of … ABSTRACT Autoimmune diseases are a set of disorders in which the immune system attacks one's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. Affecting approximately 10% of the global population, these diseases impose significant health and economic burdens worldwide. The pathogenesis of autoimmune diseases is complex, involving not only genetic predisposition (e.g., human leukocyte antigen variants), environmental triggers (e.g., infections), and a dysregulated immune response but also various interacting components that contribute to the development of diverse clinical phenotypes. This review provides a comprehensive overview of common autoimmune diseases, covering their clinical manifestations, pathogenic mechanisms, and diagnostic approaches such as disease‐specific autoantibodies. We also explore current therapeutic strategies, including commonly used broad‐spectrum anti‐inflammatory drugs, recent molecular‐targeted therapies (e.g., Janus kinase inhibitors, monoclonal antibodies), and emerging cellular therapies such as chimeric antigen receptor T cells therapy and regulatory T‐cell adoptive transfer. Incorporating knowledge from preclinical and clinical studies, this review synthesizes relevant information to inform about autoimmune diseases, bridge the gap from lab to clinic, and promote future advances through exploring precision medicine applications to meet clinical needs.

Accumulation of SA-βGal High Cells in Human Naive T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State

2025-06-14

Andreea Cristina Alexandru , Genesis Vega Hormazabal , Hiroyuki Matsui +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated β-galactosidase (SA-βGal) activity is … Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated β-galactosidase (SA-βGal) activity is a well established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naive CD4 and CD8 T cells displaying high SA-βGal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-βGal-high naive T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naive CD4 SA-βGal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naive T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.

Autoimmune associated HLAs and T cell autoantigens exhibit common patterns across several autoimmune diseases

2025-06-13

Astrid Saksager , Freja Dahl Hede , Carolina Barra | Journal of Autoimmunity

CD4+CD25+ regulatory T cell therapy in neurological autoimmune diseases

2025-06-12

Guobin Yuan , Ying Liu , Hongquan Wang +2 more | PeerJ

CD4 + CD25 + regulatory T cells (Tregs) play a critical role in maintaining immune tolerance. They are essential for the initiation and progression of autoimmune diseases affecting the nervous … CD4 + CD25 + regulatory T cells (Tregs) play a critical role in maintaining immune tolerance. They are essential for the initiation and progression of autoimmune diseases affecting the nervous system. Recently, the correlation between Tregs and neurological autoimmune diseases, as well as their therapeutic potential, has become a central focus of research. Currently, various methods for in vivo or in vitro generation and expansion of CD4 + CD25 + Tregs are under investigation; however, their application in cellular therapy is anticipated to face additional challenges. This article primarily delves into the development and function of CD4 + CD25 + Tregs, the role of Tregs in neurological autoimmune disease pathology, basic methods for enhancing therapies, and recent advancements and challenges in cellular therapy for neurological autoimmune diseases.

Immuno-amnesia: Without B cells, T cells cannot remember

2025-06-06

Jonathan S. Maltzman | Science Immunology

Why B cells are needed for optimal CD8 T cell memory. Why B cells are needed for optimal CD8 T cell memory.

Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion

2025-06-05

Helen J. Huang , Haripriya Vaidehi Narayanan , Mark Yankai Xiang +2 more | Molecular Systems Biology

Characterisation of Three Novel HLA‐DQB102 Alleles, DQB102:02:32, DQB102:251N and DQB102:256

2025-06-01

Raquel Alenda , Miguel Á. Moreno‐Hidalgo , I. Vidriales Vicente +2 more | HLA

ABSTRACT Sequencing of the novel alleles HLA‐DQB1*02:02:32 , DQB1*02:251N and DQB1*02:256 . ABSTRACT Sequencing of the novel alleles HLA‐DQB1*02:02:32 , DQB1*02:251N and DQB1*02:256 .

Molecular markers for M cells in porcine Peyer’s patches

2025-06-01

Vladimir Ginoski , Stefan Kahlert , Eva-Maria Saliu +3 more | Annals of Anatomy - Anatomischer Anzeiger

07-1: SINGLE-CELL MASS CYTOMETRY REVEALS PREPONDERANCE OF EGFR-EXPRESSING EXHAUSTED CD8+ T-CELLS IN NHPS MADE TOLERANT TO ISLET TRANSPLANTS

2025-06-01

Devanjan Dey , Adam Herman , Anna Tran +7 more | Transplantation

T cell and autoantibody profiling for primary immune regulatory disorders

2025-06-01

Emily Harris , Sarah Chamseddine , Anne H. Y. Chu +7 more | Journal of Allergy and Clinical Immunology

Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+ T cells during CNS chronic infection

2025-06-01

Aboubacar Sidiki K. Coulibaly , Lucie Nozeran , Céline Thomann +7 more | Cell Reports

Tissue-resident memory T cells (Trms) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are … Tissue-resident memory T cells (Trms) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are unclear. To investigate this, we performed single-cell transcriptomic analysis of brain CD8+ T cells from mice chronically infected with Toxoplasma gondii. This analysis revealed a heterogeneous expression of the transcriptional regulator Id2 in brain Trms, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2 deficiency in T cells caused parasite-specific Trms to develop an altered phenotype with diminished effector functions and reduced expression of the key tissue-retention molecules CD49a, CXCR6, and CD103. Furthermore, Id2 loss in brain-infiltrating CD8+ T cells led to the accumulation of exhausted PD1+Tox+CD8+ Trm cells, while Id2 overexpression repressed T cell exhaustion. Overall, our study shows that Id2 levels dictate the acquisition of effector vs. exhausted phenotypes in CD8+ Trms during chronic CNS infection.

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SINGLE CELL ANALYSIS REVEALS EXTENSIVE IMMUNE EXHAUSTION AND MEMORY‐CELL LIKE ORIGIN IN FOLLICULAR LYMPHOMA (FL) WITH INCREASED IRF4 EXPRESSION

2025-06-01

Emmanuel Contreras Guzman , Surendra Dasari , Vaishali Bhardwaj +7 more | Hematological Oncology

Narrowing Down Key Players in Autoimmunity via Single‐Cell Multiomics

2025-06-01

Altea Gjurgjaj , Cecilia Domínguez Conde | European Journal of Immunology

ABSTRACT Autoimmune diseases encompass a range of conditions in which our own immune system reacts against molecules encoded by our own genome. This phenomenon is mediated by the action of … ABSTRACT Autoimmune diseases encompass a range of conditions in which our own immune system reacts against molecules encoded by our own genome. This phenomenon is mediated by the action of antigen receptors expressed by T and B cells. Identifying the molecular events that trigger these responses as well as the effector cells that underlie them is at the heart of autoimmunity research. In this review, we discuss how single‐cell multiomics techniques applied to healthy and patient tissues are shedding light on the mechanisms underpinning autoimmune conditions, specifically by identifying disease‐associated cell states and cellular communication networks, including those linked to specific autoimmunity susceptibility genetic loci. Furthermore, we dive into the unprecedented resolution achieved in mapping autoreactive lymphocytes, a key component of autoimmune responses. We conclude with a perspective on key bottlenecks and promising future directions leveraging the latest advances in single‐cell sequencing with orthogonal methods.

KRASG12D-driven Early Pancreatic Carcinogenesis and associated Natural Killer Cell Impairment are Influenced by Sex

2025-06-01

Elise Arlt , Teresa Vauti , Andreas Schmidt +7 more | Annals of Anatomy - Anatomischer Anzeiger