Immune Regulatory Roles of Suppressor Of Cytokine Signaling (SOCS) Molecules

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Among SOCS family members, the roles of SOCS1 and SOCS3 have been extensively assessed using mouse models of genetic deletion. Whether there is a redundancy between SOCS1 and SOCS3 is unclear, mostly because mouse models of SOCS1/SOCS3 double deficiency have not been available. Thus, we aimed to generate SOCS1, SOCS3-double deficient mice by using SOCS1-floxed and SOCS3-floxed mice, and by breeding them with T cell specific Cre recombinase transgenic mice. We have been breeding these mice for more than a year, but still did not achieve the desired genotypes. But, by expanding the breeding, we hope to obtain T cell specific SOCS1/SOCS3-deficient mice anytime soon for their in-depth analyses. In parallel to SOCS1 and SOCS3, our study also has been focused on SOCS4 which remains a poorly characterized SOCS family that is abundantly expressed in immature thymocytes but whose expression is downregulated on mature T cells. We recently generated SOCS4-deficient mice utilizing a gene-trap ES cell system, and we verified the lack of SOCS4 mRNA expression in these mice by real-time reverse transcription PCR. Gross phenotypic analysis of SOCS4-deficient mice did not show abnormalities in their development, and we also did not observe any adverse effect of SOCS4-deficiency in their immune system. Moreover, IL-7 signaling remained unaffected in SOCS4-deficient T cells, suggesting a potential redundancy of SOCS4 with other SOCS family members. Thus, we are also in the process of generating SOCS4, SOCS1 double deficient and SOCS4, SOCS3 double deficient mice to examine these points. Conversely, to examine if the forced overexpression of SOCS4 would affect cytokine signaling, we generated T cell-specific SOCS4-transgenic mice. Here, we found that SOCS4 overexpression suppressed the development and differentiation of T cells. Specifically, we found that transgenic SOCS4 expression interfered with T cell survival and homeostasis so that naive T cell numbers in peripheral lymphoid tissues were significantly reduced. The molecular basis of the detrimental effect of SOCS4 on T cells, however, remains unclear because we found that cytokine signaling was unaffected in SOCS4 transgenic T cells. We previously reported that the nuclear factor ThPOK upregulates the transcription of SOCS1 and SOCS3 in T cells [Luckey MA et al., 2014, Nat. Immunol.]. Because ThPOK is only expressed in CD4 T cells and absent in CD8 T cells and immature thymocytes, it has been unclear how SOCS1 is induced in CD4, CD8 double positive thymocytes or in CD8 T cells. To this end, we have recently shifted our interest to CD4+CD8aa+ intraepithelial T cells in the small intestine, which are derived from CD4 T cells but then differentiate into CD4+CD8aa+ T cells in the gut. Importantly, the conversion of CD4 T cells into CD4+CD8aa+ T cells is mediated by the loss of ThPOK and the acquisition of the CD8 lineage specifying factor Runx3d. How the expression of SOCS family molecules changes during this process is not known. But, we considered this an interesting new venue to gain insights into the regulatory process of SOCS family molecule expression along the ThPOK/Runx3d expression pathway. Thus, we performed a series of studies to understand what controls the generation of CD4+CD8aa+ intraepithelial T cells, and we identified the chemokine receptor CCR9 as a new regulator of this process (Li C. et al., 2022, Mucosal Immunol.), and we also found homeostatic IL-7 and IL-15 signaling as suppressors of this T cell conversion (Li C. et al., 2022, Cell Mol Immunol.). Equipped with these new insights, we are currently assessing the role of SOCS family members in the differentiation and maintenance of T cells in the gut, but also in other non-lymphoid tissues.