Role of Foxo1 in T cell Activation and Survival

Abstract

FOXO1 is a transcription factor, a member of a class of evolutionary conserved forkhead genes that also includes Foxo3a, Foxo4, and Foxo6. FOXOs regulate the expression of apoptotic, cell cycle progression, and detoxification genes. In response to growth factor signaling, FOXOs are phosphorylated and excluded from the nucleus to prevent their transcriptional activity. FOXOs have been extensively studied and shown to be important in longevity and cancer. FOXO1 is highly expressed in humans and mice; however, its function in T cells has not been examined. Foxo1 was conditionally deleted in T cells, Foxo1 KO mice displayed a higher proportion of activated T cells. In addition, Foxo1 KO mice had an increased number of CD4+ but not CD8+ T cells in lymph node and spleen. Upon activation, FOXO1 KO T cells, proliferated, yet failed to accumulate due to impaired survival. This accumulation defect after activation was also observed in FOXO1 KO TCR transgenic T cells. When we examined the role of FOXO1 in survival and cytokine rescue in activated CD4+ T cells, we observed that FOXO1 KO CD4+ T cells were less sensitive to growth factor withdrawal induced apoptosis. This FOXO1‐mediated survival effect can be partially attributed to decreased levels of Bim expression. These findings demonstrate that FOXO1 plays a very important role in regulating T cell activation and survival.