IL-2 signaling shapes patterns of Interferon Regulatory Factor 8 expression in CD8 T cells 4824

Abstract Description Two closely related members of the interferon regulatory factor (IRF) family of transcription factors, IRF4 and IRF8, have been described to reinforce divergent cell states in dendritic cells, B cells and macrophages. Although IRF4 has been recognized to critically support CD8 T cell differentiation, little is known mechanistically of the role of IRF8 in this process. Using OT-1 CD8 T cells, we show that unlike IRF4, IRF8 exhibits a biphasic pattern of induction upon T-Cell Receptor (TCR) engagement that is highly sensitive to JAK-STAT inhibition and less shaped by TCR signal strength. At the peak of OVA-expressing Listeria monocytogenes infection, OT-1 cells that produced IL-2 upon restimulation expressed more IRF4 and less IRF8 than their non-IL-2 producing counterparts (IL-2 responders). In the absence of TCR stimulation, ex-vivo Cytotoxic T Lymphocytes rested in IL-2 alone induced IRF8 but not IRF4 in a dose-dependent manner. In models of antigen persistence such as MC38 tumors, preliminary data indicate an enrichment of IRF8-expressing CD8+ Tumor Infiltrating Lymphocytes (TILs) in the Granzyme B expressing cells, while no such enrichment was observed for IRF4. In summary, the response of IRF8 to IL-2 signaling and its prevalence in tumor infiltrating lymphocytes suggests its potential as a target for immunotherapy. Funding Sources Supported by NIH R01AI132419-03 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)