CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responses

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Abstract
Both CD4+ T cell help and IL-2 have been postulated to “program” activated CD8+ T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8+ T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4+ T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8+ T cells peaked 3–4 days after initial priming and was dependent on CD4+ T cell help, likely through a CD28:CD80/86 mediated pathway. CD4+ T cell or CD25-deficiency led to normal early effector CD8+ T cell differentiation, but a subsequent lack of accumulation of CD8+ T cells resulting in overall decreased memory cell generation. Interestingly, in both primary and recall responses KLRG1high CD127low short-lived effector cells were drastically diminished in the absence of IL-2 signaling, although memory precursors remained intact. In contrast to previous reports, upon secondary antigen encounter CD25-deficient CD8+ T cells were capable of undergoing robust expansion, but short-lived effector development was again impaired. Thus, these results demonstrated that CD4+ T cell help and IL-2 signaling were linked via CD25 up-regulation, which controls the expansion and differentiation of antigen-specific effector CD8+ T cells, rather than “programming” memory cell traits.