Cutting Edge: TGF-β1 and IL-15 Induce FOXP3+ γδ Regulatory T Cells in the Presence of Antigen Stimulation

Casetti, Rita; Agrati, Chiara; Wallace, Marianne; Sacchi, Alessandra; Martini, Federico; Martino, Angelo; Rinaldi, Alessandra; Malkovsky, Miroslav

doi:10.4049/jimmunol.0901334

Cited by 151 publications

(141 citation statements)

References 35 publications

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“…Depending on the culture conditions, Vc9/Vd2 T cells clearly assume different functions including distinct cytokine profiles [49,74,72,[124][125][126], and hence more research is needed to delineate whether Vc9/Vd2 T-APCs may induce different 'flavors' of CD4 + T cell responses (Th1, Th2, Th17, Th22, Treg), and what the signals involved in such a polarization are. In this respect, our preliminary findings suggest that under appropriate conditions Vc9/Vd2 T-APCs are able to induce considerable IL-22 expression in naive CD4 + T cells [C.J.T., M.E.…”

Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

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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Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

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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“…In these trials, IL-2 also elevated the frequency of Tregs, which can inhibit cd T-cell responses or even induce regulatory cd T cells, according to in vitro experiments. 47,48 The reverse situation, however, might also occur in these patients, as phosphoantigen-activated cd T cells can overcome Tregs 49 and TGF-b immunosuppressive functions. 50 The above trials demonstrated that Tregs were not significantly induced by these regimens involving only low doses of IL-2, and they did not offer evidence of Treg-based cd T-cell immunosuppression.…”

Section: Safety Of CD T-cell Activation In Patientsmentioning

confidence: 99%

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

et al. 2012

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During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human cd T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of cd T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of cd T cell-based strategies in the current landscape of cancer immunotherapies.

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“…Importantly, however, they can be skewed towards distinct effector functions depending on the microenvironment, in analogy to, and even beyond, the emerging plasticity of CD4 1 ab cells. As such, under appropriate culture conditions, Vg9/Vd2 T cells divert from the 'default' Th1/CTL-like phenotype and assume features reminiscent of Th2 cells [27,29], Th17 cells [30,31], Treg cells [32] and even professional APCs [33]. Our earlier microarray studies revealed that Vg9/Vd2 T cells express a range of T FH -associated molecules when stimulated with HMB-PP in the presence of IL-21 suggesting a potential role in the GC reaction [27].…”

Section: Introductionmentioning

confidence: 99%

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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Cutting Edge: TGF-β1 and IL-15 Induce FOXP3+ γδ Regulatory T Cells in the Presence of Antigen Stimulation

Cited by 151 publications

References 35 publications

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

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

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

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

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