Soluble γc cytokine receptor suppresses IL-15 signaling and impairs iNKT cell development in the thymus

Abstract

The soluble γc protein (sγc) is a naturally occurring splice isoform of the γc cytokine receptor that is produced by activated T cells and inhibits γc cytokine signaling. Here we show that sγc expression is also highly upregulated in immature CD4+CD8+ thymocytes but then downregulated in mature thymocytes. These results indicate a developmentally controlled mechanism for sγc expression and suggest a potential role for sγc in regulating T cell development in the thymus. Indeed, sγc overexpression resulted in significantly reduced thymocyte numbers and diminished expansion of immature thymocytes, concordant to its role in suppressing signaling by IL-7, a critical γc cytokine in early thymopoiesis. Notably, sγc overexpression also impaired generation of iNKT cells, resulting in reduced iNKT cell percentages and numbers in the thymus. iNKT cell development requires IL-15, and we found that sγc interfered with IL-15 signaling to suppress iNKT cell generation in the thymus. Thus, sγc represents a new mechanism to control cytokine availability during T cell development that constrains mature T cell production and specifically iNKT cell generation in the thymus.

Soluble γc receptor attenuates anti‐tumor responses of CD8+ T cells in T cell immunotherapy

“…sγc has previously been shown to skew CD4 + T cells to Th17 by dampening IL‐2 signals and suppress NKT cell development by downregulating of IL‐15 signals . Here, we have confirmed these previous study findings, and went a step further by showing that sγc deficiency could augment IFNγ, TNFα and ganzyme B expressions of activated CD8 + T cells.…”

“…Indeed, we found that sγc directly interacts with membrane IL‐2 receptors and interfere with ligand/receptor interaction. Altogether with current study and our previous reports, we propose that sγc produced upon TCR stimulation competes with mγc to bind IL‐2Rβ and opposes formation of signaling competent heterotrimeric IL‐2/IL‐2Rβ/mγc complexes. In fact, recent reports using immunofluorescence co‐patching and FRET analysis documented that mγc and IL‐2Rβ already can form 1:1 heterodimeric complexes even in the absence of IL‐2 .…”

“…In this study, we investigated the role of sγc on the effector functions and survival of CD8 + T cells against tumor. We have previously shown an antagonistic effect of sγc on IL‐2 and IL‐15 signaling . Consistent with this, we found that sγc dampened IL‐2 and IL‐15 signaling and induced the suboptimal effector functions and survival of CD8 + T cells by showing that sγc could inhibit the function of TCR stimulated CD8 + T cells, not only by significantly reducing the production of Th1 cytokine IFNγ but also by inflammatory cytokines TNFα and granzyme B; sγc deficient CD8 + T cells demonstrated superior anti‐tumor responses and persistence in recipient mice.…”

“…We sought to determine the role of sγc in CD8 + T cell response, as sγc negatively regulated the γc cytokines IL‐2 and IL‐15 which are important in optimal CD8 + T cell responses. We first examined and compared the kinetics of sγc, IL‐2, IFNγ, TNFα, CD69 and CD25 expression of CD8 + T cells following TCR stimulation to clarify regulatory function of sγc in the context of complex cellular immune responses.…”

“…Recently, we identified sγc as an antagonistic regulator for γc cytokines, including IL‐2, IL‐7 and IL‐15, which is important in T cell homeostasis and activation, especially, in the survival, proliferation and effector function of CD8 + T cells . sγc is generated via alternative splicing of γc mRNA, which can then be translated to a truncated form of membrane γc (mγc), and the secreted sγc protein forms a homodimeric structure that binds directly to IL‐2Rβ, another subunit of the cytokine receptors, resulting in the inhibition of IL‐2 and IL‐15 signaling . The proliferation of naïve CD8 + T cells that is responsible to IL‐2 unlike CD4 + T cells were significantly inhibited by sγc .…”