FoxO3 is a negative regulator of primary CD8(+) T cell expansion but not of memory formation

The generation of CD8(+) T cells by vaccination represents an important goal for protective immunity to infectious pathogens. It is thus of utmost importance to understand the mechanisms involved in the generation of optimal CD8(+) T cell responses. The forkhead box O (FoxO) family of transcription factors plays a crucial role in cellular responses to environmental change. Among them, FoxO3 is critically involved in the regulation of cellular proliferation, apoptosis, metabolism, and stress resistance to withdrawal of nutrients or cytokine growth factors. Since the role of FoxO3 has been poorly studied in the immune system, here we have evaluated its involvement in the CD8(+) T cell response. We observe that CD8(+) T cells deficient for FoxO3 undergo a significantly greater primary expansion than their wild-type counterparts in response to both infectious (vaccinia virus) or non-infectious (non replicating cellular vaccine) immunogens, resulting in a larger cohort of cells following contraction. These survivors, however, do not undergo a greater secondary response than wild type. Taken together, our data show that FoxO3 is a negative regulator of the CD8(+) T cells response, specifically during the primary expansion.