Suppressor of cytokine signaling proteins are induced by IL-7 and regulate CD127 expression in human CD8 T cells (P6291)

Abstract

Interleukin (IL)-7 is an essential non-redundant cytokine influencing cell survival and proliferation throughout the life-span of a T cell. IL-7 is currently being investigated as a potential therapy in HIV+ individuals with poor immunological response to antiretroviral therapy. In order to optimize the use of IL-7 in therapeutic settings, it is crucial to understand how expression of the IL-7 receptor-α (CD127) is regulated. We elucidate in this study the mechanism by which IL-7 targets surface CD127 protein for degradation and describe the role of SOCS proteins, a family of eight proteins (CIS and SOCS1-7), in this process. We show here that in primary human CD8 T cells, upon binding IL-7, surface CD127 is rapidly internalized and phosphorylated at Y449 within 20 minutes of IL-7 stimulation, while activation of the JAK/STAT5 pathway stimulates expression of CIS transcripts and proteins. Following IL-7 stimulation, CIS binds directly to CD127 as demonstrated by Co-IP and co-localizes with both CD127 and the early endosomal marker EEA1, then with the proteasomal marker MCP20, as demonstrated by confocal microscopy. Subsequent proteasomal degradation of CD127 and CIS is dependent on an E3 ligase and can be blocked with the E3 ligase inhibitor SMER3. Through siRNA-mediated knockdowns we confirm roles of CIS in the IL-7 mediated degradation of the CD127 protein.