Cytokine induced SH2-containing (CIS) protein mediated intrinsic and extrinsic CD8+ T cell regulation

Abstract

Abstract Small nuclear polymorphisms in CIS exhibit strong correlation with enhanced disease susceptibility in humans. CIS is a member of the SOCS family of proteins, and SOCS proteins are intracellular negative regulators of JAK/STAT signalling. The SH2 domain of CIS inhibits STAT5 interaction with JAK1 and JAK3. STAT5 is critical in downstream signalling of IL-2 and IL-15 in CD4+ and CD8+ T cells. IL-2 and IL-15 signalling are important in the regulation of critical T cell checkpoints including activation, proliferation, survival and differentiation. The regulatory role of CIS in immune cell development and function is relatively undefined, and recent studies have provided brief insights on the role of CIS in CD8+ T cell biology and its overall contribution to infection and immunity. Using CIS knock-out mice, we show that CIS plays a significant role in intrinsic and extrinsic regulation of CD8+ T cell responses to influenza A virus infection. Infection in the absence of CIS results in reduced morbidity and improved recovery compared with wildtype mice associated with enhanced recruitment of influenza A virus specific CD8+ T cells in the lungs of knockout mice. The observed changes in influenza A virus specific CD8+ T cells is supported by intrinsic modification of the proliferative capacity of CD8+ T cells lacking CIS. We also observe significant changes in DC subsets in the lung and mediastinal lymph nodes altering the extrinsic regulation of influenza specific CD8+ T cells. This work highlights a comprehensive understanding of the role of CIS in viral immunity and CD8+ T cell biology.