γδ T-cell help in responses to pathogens and in the development of systemic autoimmunity

Li, Wen; Hayday, Adrian

doi:10.1007/bf02786392

Cited by 22 publications

(20 citation statements)

References 75 publications

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“…Earlier studies in mice demonstrated that GC reactions that solely depend on gd T cells are somewhat inefficient and result in relatively high titres of class-switched, self-reactive antibodies [12,44]. gd T cells may thus provide general B-cell help and enhance humoral immune responses, while MHC-restricted ab T cells ensure antigen specificity by regulating affinity maturation and clonal selection.…”

Section: Discussionmentioning

confidence: 99%

“…gd T cells support antibody production in immunised and infected mice [11][12][13]. Of note, GCs are present in TCR-a À/À and TCR-b À/À mice and develop in SCID mice upon adoptive transfer of gd T cells and B cells, demonstrating that gd T cells are sufficient to orchestrate follicular responses [14][15][16].…”

Section: Introductionmentioning

confidence: 97%

“…gd T cells support antibody production in immunised and infected mice [11][12][13] 110 [17,18], where they are scattered throughout the T zone and clustered within GCs [8]. Early studies in lupus patients led to the isolation of human gd T-cell lines capable of inducing autoantibody production by autologous B cells [19].…”

Section: Introductionmentioning

confidence: 99%

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IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

et al. 2011

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Vc9/Vd2 T cells are a minor subset of T cells in human blood and differ from all other lymphocytes by their specific responsiveness to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a metabolite produced by a large range of microbial pathogens. Vc9/Vd2 T cells can be skewed towards distinct effector functions, in analogy to, and beyond, the emerging plasticity of CD4 1 T cells. As such, depending on the microenvironment, Vc9/Vd2 T cells can assume features reminiscent of Th1, Th2, Th17 and Treg cells as well as professional APCs. We here demonstrate that Vc9/Vd2 T cells express markers associated with follicular B helper T (T FH ) cells when stimulated with HMB-PP in the presence of IL-21. HMB-PP induces upregulation of IL-21R on Vc9/Vd2 T cells. In return, IL-21 plays a co-stimulatory role in the expression of the B-cell-attracting chemokine CXCL13, the CXCL13 receptor CXCR5 and the inducible co-stimulator by activated Vc9/Vd2 T cells, and enhances their potential to support antibody production by B cells. The interaction between HMB-PP-responsive Vc9/Vd2 T cells, IL-21-producing T FH cells and B cells in secondary lymphoid tissues is likely to impact on the generation of high affinity, class-switched antibodies in microbial infections. Key words: Bacterial infections . B cells . cd T cells . IL-21 . T FH cells IntroductionThe establishment of long-term humoral immunity depends on the production of high-affinity antibodies capable of neutralising and opsonising invading pathogens. These antibodies are generated through somatic hypermutation, class switch recombination and affinity maturation of activated B cells, processes that take place in the germinal centres (GCs) of secondary lymphoid organs and depend on cognate help provided by CD4 1 follicular B helper T (T FH ) cells [1,2]. Human T FH cells are defined by the expression of characteristic markers [3][4][5][6][7]: the transcriptional repressor Bcl-6 that directs T FH lineage commitment; the chemokine receptor CXCR5 that enables T FH cells to migrate into the B-cell follicles; the CXCR5 ligand CXCL13 that attracts further CXCR5 1 cells such as naïve B cells and early activated CD4 1 T cells; the co-stimulatory molecules, inducible co-stimulator (ICOS) and programmed cell death 1 (PD-1), which interact with their corresponding ligands on B cells; and the cytokine IL-21 that steers B-cell differentiation and antibody production. Murine T FH cells express the same panel of markers with the exception of CXCL13.While the crucial role of T FH cells in providing B-cell help is undisputed, other T-cell subsets including CD8 1 T cells, NKT cells and gd T cells contribute to the outcome of humoral immune responses [8][9][10]. gd T cells support antibody production in immunised and infected mice [11][12][13] 110 [17,18], where they are scattered throughout the T zone and clustered within GCs [8]. Early studies in lupus patients led to the isolation of human gd T-cell lines capable of inducing autoantibody production by autologous B cells [19]. Subsequent ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

et al. 2011

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“…Similarly, patients with selective deficiencies in ab T cells due to mutations in recombinase activating gene 1 (RAG1), TCRa subunit constant gene (TRAC) or CD3D show normal or even elevated levels of antibody production [102][103][104]. Functional proof that cd T cells are sufficient to orchestrate follicular responses came from adoptive transfer experiments in SCID mice [105,106].…”

Section: Provision Of B Cell Help: Boosting Humoral Immunitymentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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“…Although TCR ␣-or ␤-deficient mice have been extensively studied in various models of autoimmunity and parasite infections (reviewed in Ref. 19), the question of whether ␥␦ T cells can independently support Ig SHM has never been answered.…”

Section: Ig Shm Takes Place In Gcs Of Tcr ␤-Deficient Micementioning

confidence: 99%

Cutting Edge: γδ T Cells Provide Help to B Cells with Altered Clonotypes and Are Capable of Inducing Ig Gene Hypermutation

Zheng

Marinova

Han

et al. 2003

The Journal of Immunology

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It has not been resolved whether γδ T cells can collaborate with germinal center B cells and support Ig hypermutation during an Ab response to a truly defined T-dependent Ag. In this study, we show that in the absence of αβ T cells, immunization with the well-defined T-dependent Ag, (4-hydroxy-3-nitrophenyl) acetyl (NP) conjugate, was able to induce Ig hypermutation. However, the clonotypes of B cells responding to NP were dramatically altered in TCR β−/− mice. Unlike B cells in wild-type mice that use canonical VDJ rearrangements, most NP-responding B cells in mutant mice use analog genes of the J558 gene family. In addition, the majority of anti-NP Abs produced in mutant mice use κL chain instead of λ1L chain, which dominates in mice of Ighb background. Thus, the B cell population that collaborates with γδ T cells is distinct from B cells interacting with conventional αβ Th cells.

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γδ T-cell help in responses to pathogens and in the development of systemic autoimmunity

Cited by 22 publications

References 75 publications

IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

IL‐21 enhances the potential of human γδ T cells to provide B‐cell help

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Cutting Edge: γδ T Cells Provide Help to B Cells with Altered Clonotypes and Are Capable of Inducing Ig Gene Hypermutation

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