Interleukin 7 Up-regulates CD95 Protein on CD4+ T Cells by Affecting mRNA Alternative Splicing

Interleukin-7 (IL-7) has been used as an immunoregulatory and latency-reversing agent in human immunodeficiency virus type 1 (HIV-1) infection. Although IL-7 can restore circulating CD4 + T cell counts in HIV-1-infected patients, the anti-apoptotic and proliferative effects of IL-7 appear to benefit survival and expansion of HIV-1-latently infected memory CD4 + T lymphocytes. IL-7 has been shown to elevate CD95 on CD4 + T cells in HIV-1-infected individuals and prime CD4 + T lymphocytes to CD95-mediated proliferative or apoptotic signals. Here we observed that through increasing microRNA-124, IL-7 down-regulates the splicing regulator polypyrimidine tract binding protein (PTB), leading to inclusion of the transmembrane domain-encoding exon 6 of CD95 mRNA and, subsequently, elevation of CD95 on memory CD4 + T cells. Moreover, IL-7 up-regulates cellular FLICE-like inhibitory protein (c-FLIP) and stimulates c-Jun N-terminal kinase (JNK) phosphorylation, which switches CD95 signaling to survival mode in memory CD4 + T lymphocytes. As a result, co-stimulation through IL-7/IL-7R and FasL/CD95 signal pathways augments IL-7-mediated survival and expansion of HIV-1-latently infected memory CD4 + T lymphocytes. Collectively, we have demonstrated a novel mechanism for IL-7-mediated maintenance of HIV-1 reservoir.IL-7 can up-regulate CD95 expression on memory CD4 + T cells, but the mechanism remains unclear. Results IL-7 elevates miR-124 to decrease the expression of splicing regulator PTB and represses CD95 mRNA splicing. Conclusion IL-7 elevates CD95 expression by regulating its alternative splicing. Significance Our data demonstrate that the co-stimulation of IL-7 and CD95 ligand benefits HIV-1 reservoir maintenance.