Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell‐contact‐dependent and sensitive to GITR modulation

Abstract

cd T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of cd-T-cell-based cancer therapies. Thus, the regulation of cd-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4 1 CD25 1 ab T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of cd T cells, namely the production of the pro-inflammatory cytokines, IFN-c and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and cd T cells, results in the induction of an anergic state in cd lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of cd T cells are regulated. IntroductionThe integration of multiple effector and regulatory mechanisms dictates the course of immune responses to self and non-self antigens. gd T cells are innate-like lymphocytes known to mount robust responses to infectious pathogens [1] and tumors [2], while also regulating tissue homeostasis and repair [3]. Importantly, several of these functions are non-redundant, as demonstrated by the immunopathology phenotypes of TCR-d-deficient mice [4]. It is also well documented that upon pathogen challenge (for example, with Plasmodium falciparum, Mycobacterium tuberculosis, Haemophilus influenzae, or Streptococcus pneumoniae), gd T cells are one of the immune populations that expands most dramatically in human peripheral blood [1,5,6].In contrast with adaptive ab T cells, activated gd lymphocytes are capable of ''immediate'' cytotoxicity and cytokine secretion [5]. In fact, we have recently shown that murine gd T cells become functionally competent in the thymus, particularly regarding the production of pro-inflammatory cytokines . Furthermore, several reports have demonstrated the crucial contributions of gd T cells to the reservoirs of such cytokines in the context of anti-tumor immunity [8], immune responses to infection [9], and autoimmunity [9,10]. While these data highlight the importance of understanding how the [17], and monocytes/macrophages [18]. As a result, CD4 1 CD25 1 ab T cells, and particularly those that develop in the thymus through a Foxp3-dependent genetic program [19,20], so-called ''naturally occurring '' Treg (nTreg), are pivotal to maintaining immune homeostasis and preventing inflammatory and autoimmune diseases [21]. On the other hand, Treg-suppressive functions are also known to diminish immunity to pathogens and to tumors [22,23]. Provocatively, an inverse correlation between circulating human Treg frequencies and gd-T-cell numbers in cancer patients has been recently reported [24].Building on these foundations, we show here that Treg suppress gd-T-cell ...

CD4+Foxp3+ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

“…This finding is consistent with a recent study showing that T REG cells inhibit gd T-cell proliferation in vitro [32,40]. It is possible that the more potent T REG -cell suppression of IL-17 secretion compared with IFN-g secretion seen in the mucosal tissue occurs as a result of a more profound inhibition of gd T-cell expansion in situ.…”

“…A significant role of IL-17-producing gd T cells in the exacerbation of the autoimmunity has also been observed in the mouse models of experimental autoimmune encephalomyelitis [37] and collagen-induced arthritis [30]. While some recent studies suggest that T REG cells can suppress some aspects of human or mouse gd T-cell functions [32,[38][39][40], the dynamics and impact of this regulation on gd T-cell function throughout IBD development is ill-defined. In this study, we investigate the functional dynamics of Foxp3 …”

Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals

“…S6). In addition, unconventional T cells, such as NKT or γδT cells, may be involved in antitumor effects of anti-CTLA-4/anti-GITR mAb combination treatment, because it has been shown that the GITR signal also stimulates these T cells (32)(33)(34).…”

B7–CD28 Costimulatory Signals Control the Survival and Proliferation of Murine and Human γδ T Cells via IL-2 Production

“…Infection by Plasmodium is known to cause striking expansions of gd cells both in mice (20)(21)(22) and in humans (23)(24)(25)(26). In fact, in patients infected with either Plasmodium falciparum (23,24) or Plasmodium vivax (25), gd cells frequently expand to 30-40% of all peripheral blood T cells (compared with 1-5% in healthy donors).…”