Differential Requirements For Irf4 In The Clonal Expansion And Homeostatic Proliferation Of Naive And Memory Murine Cd8(+) Tcells

Interferon regulatory factor 4 (IRF4) has critical roles in immune cell differentiation and function and is indispensable for clonal expansion and effector function in Tcells. Here, we demonstrate that the AKT pathway is impaired in murine CD8(+) Tcells lacking IRF4. The expression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT pathway, was elevated in Irf4(-/-) CD8(+) Tcells. Inhibition of PTEN partially rescued downstream events, suggesting that PTEN constitutes a checkpoint in the IRF4-mediated regulation of cell signaling. Despite the clonal expansion defect, in the absence of IRF4, memory-like CD8(+) Tcells could be generated and maintained, although unable to expand in recall responses. The homeostatic proliferation of naive Irf4(-/-) CD8(+) Tcells was impaired, whereas their number eventually reached a level similar to that of wild-type CD8(+) Tcells. Conversely, memory-like Irf4(-/-) CD8(+) Tcells underwent homeostatic proliferation in a manner similar to that of wild-type memory CD8(+) Tcells. These results suggest that IRF4 regulates the clonal expansion of CD8(+) Tcells at least in part via the AKT signaling pathway. Moreover, IRF4 regulates the homeostatic proliferation of naive CD8(+) Tcells, whereas the maintenance of memory CD8(+) Tcells is IRF4-independent.