Differential requirements for IRF4 in the clonal expansion and homeostatic proliferation of naive and memory murine CD8+ T cells

Abstract

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

Keywords: CD8+ T cells; Homeostasis; Memory cell; Signal transduction; Transcription factors.