Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7R alpha-expressing cells.

The common gamma chain cytokines interleukin (IL)-2 and IL-7 are important regulators of T cell homeostasis. Although IL-2 is implicated in the acute phase of the T cell response, IL-7 is important for memory T cell survival. We asked whether regulated responsiveness to these growth factors is determined by temporal expression of the cytokine-specific IL-2 receptor (R) alpha and IL-7Ralpha chains. We demonstrate that IL-2Ralpha is expressed early after priming in T cell receptor-transgenic CD4(+) T cells, whereas IL-7Ralpha expression is lost. In the later stage of the response, IL-7Ralpha is reexpressed while IL-2Ralpha expression is silenced. This reciprocal pattern of IL-2Ralpha/IL-7Ralpha expression is disturbed when CD4(+) T cells are primed in the absence of IL-2 signals. Primed IL-2(-/-) or CD25(-/-) (IL-2Ralpha(-/-)) CD4(+) T cells, despite showing normal induction of activation markers and cell division, fail to reexpress IL-7Ralpha late in the response. Because the generation of CD4(+) memory T cells is dependent on IL-7-IL-7Ralpha interactions, primed IL-2(-/-) or CD25(-/-) CD4(+) T cells develop poorly into long-lived memory cells. Retrovirus-mediated expression of IL-7Ralpha in IL-2(-/-) T cells restores their capacity for long-term survival. These results identify IL-2 as a factor regulating IL-7Ralpha expression and, consequently, memory T cell homeostasis in vivo.