T cell homeostasis requires G protein‐coupled receptor‐mediated access to trophic signals that promote growth and inhibit chemotaxis

Abstract

Signals that regulate T cell homeostasis are not fully understood. G protein-coupled receptors (GPCR), such as the chemokine receptors, may affect homeostasis by direct signaling or by guiding T cell migration to distinct location-restricted signals. Here, we show that blockade of Gai-associated GPCR signaling by treatment with pertussis toxin led to T cell atrophy and shortened life-span in T cell-replete hosts and prevented T cell homeostatic growth and proliferation in T cell-deficient hosts. In vitro, however, neither GPCR inhibition nor chemokine stimulation affected T cell atrophy, survival, or proliferation. These findings suggest that GPCR signals are not trophic stimuli, but instead may be required for migration to distinct trophic signals, such as IL-7 or selfpeptide/MHC. Surprisingly, while chemokines did not affect atrophy, atrophic T cells displayed increased chemokine-induced chemotaxis that was prevented by IL-7 and submitogenic anti-CD3 antibody treatment. This increase in migration was associated with increased levels of GTP-bound Rac and the ability to remodel actin. These data suggest a novel mechanism of T cell homeostasis wherein GPCR may promote T cell migration to distinct location-restricted homeostatic trophic cues for T cell survival and growth. Homeostatic trophic signals, in turn, may suppress chemokine sensitivity and cytoskeletal remodeling, to inhibit further migration. IntroductionMaintenance of lymphocyte homeostasis is crucial to allow rapid protective responses to foreign pathogens and simultaneously prevent diseases of the immune system, such as autoimmunity or immunodeficiency. One mechanism to maintain immune homeostasis is the requirement of cells to receive signals from their microenvironment to prevent activation of a default cell-intrinsic death pathway [1]. When deprived of these signals, cells undergo cellular atrophy prior to an ultimate commitment to apoptosis. Atrophy is characterized by decreased cell size and metabolism and inhibition of the cell cycle [2][3][4]. A second mechanism to maintain immune homeostasis is the spontaneous proliferation of lymphocytes in lymphopenic animals [5]. This cytokine and self-antigen-driven cell expansion may play an important role to increase lymphocyte numbers when they are limiting. A third homeostatic process is regulation of T cell migration to allow even T cell distribution and immunosurveillance [6,7]. Lymphocyte chemotaxis is guided primarily by Gaiassociated G protein-coupled receptor (GPCR) signaling mediated by chemokine receptors [7]. The c c cytokine IL-7 and interactions between the TCR and self-peptide/MHC maintain T cell viability, allow homeostatic proliferation in vivo and can maintain basal T cell size and metabolism in vitro [3,5,8,9]. The role of GPCR in these T cell homeostatic processes, however, is not known. These signals may directly affect T cell homeostasis through activation of similar signaling pathways as activated by c c cytokines and the TCR. In particular, the survival-promoting phosphatidylinosit...

Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor

“…Previous studies have shown that culturing T cells in absence of any stimulation also induces an increase in the surface expression of L-selectin on both CD4 + and CD8 + T cells42, although the expression of CCR7 does not seem to be affected43. Considering our previous results, we analyzed the role of Foxo1 in these effects and observed that growth factor withdrawal induces a similar Foxo1-dependent increase in the expression of Sell and Klf2 mRNA in naive T cells (Fig.…”

IL-7/anti–IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R

“…8 Accordingly, depriving T cells of access to secondary lymphoid tissue impairs their ability to survive or proliferate in response to endogenous homeostatic factors. 32,33 Interestingly, the results in this article suggest that access to the T-cell zones is also a requisite to optimally respond to exogenous IL-7. Although intraperitoneal injection results in a systemic distribution of the inoculum, the effect of the IL-7/M25 was largely targeted to T cells that have direct access to the T-cell zones.…”

“…PTX neutralizes Ga i protein-coupled receptors such as CCR7 and prevents homing of T cells to the LNs and white pulp of the spleen. [32][33][34] Reciprocally, FTY720, a sphingosine analog, disrupts sphingosine-1-phosphate receptor function and prevents egress of T cells from lymphoid tissues. [35][36][37] The effect of PTX was analyzed by measuring the response of T cells pretreated with PTX.…”

“…Figure 1B). Furthermore, it is known that PTX treatment does not impose a general restriction on T-cell proliferation, 32,33 although it inhibits T-cell homing into the LNs ( Figure 1C). Similarly, CCR7…”

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

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