IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response

Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8(+) T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8(+) T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1(hi)CD127(lo) CD8(+) T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1(lo)CD127(hi) cells. While IL-7 and IL-15 both induced proliferation of KLRG1(lo) cells, KLRG1(hi) cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1hi CD8(+) T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1(hi) CD8(+) T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer. (Blood. 2008; 112:3704-3712)