Interleukin-7 Receptor Signaling Is Deficient in CD4+ T Cells from HIV-Infected Persons and Is Inversely Associated with Aging

Interleukin-7 (IL-7) plays an important role in T cell development and survival. Mice engineered with IL-7 [1] or IL-7 receptor gene deletions [2, 3] are lymphopenic and humans with IL-7 receptor α deficiencies also experience immunodeficiency [4]. IL-7 enhances thymocyte survival [5, 6] and is required for survival of memory and naive T cells [7–9]. Thus, perturbations in IL-7 and/or the IL-7 receptor are likely to have important consequences for immune homeostasis. IL-7 receptor expression is diminished in cells from HIV-infected persons [10, 11], raising the possibility that IL-7 receptor signaling may be impaired in HIV disease. Our previous studies explored the effects of IL-7 stimulation on naive CD4+ T cells from HIV-infected persons during T cell receptor–driven cellular proliferation [12]. Our results suggested that naive T cells from HIV-infected persons responded to IL-7 stimulation with an intensity similar to that of cells from healthy control subjects. However, we did not directly measure IL-7 responsiveness in the absence of T cell receptor stimulation, nor did we investigate the signaling function of the receptor. To mediate signaling, IL-7 interacts with the IL-7 receptor complex, consisting of the α chain (CD127) and the common γ chain, which is shared by several other cytokine receptors, including those for IL-2 and IL-15. Binding of IL-7 to the receptor results in activation of JAK3 and JAK1, which then leads to phosphorylation of signal transducer and activator of transcription (STAT) molecules, including STAT5 [13]. The importance of STAT5 signaling in T cell homeostasis has been demonstrated in transgenic mice, in which overexpression of STAT5b results in increased spontaneous proliferation of naive CD4+ and CD8+ T cells [14, 15]. Furthermore, mice with STAT5 gene deletion have reduced numbers of peripheral T lymphocytes [16, 17]. Thus, IL-7–mediated STAT5 activation is an important component to normal T cell homeostasis. To examine the signaling response of CD4+ T cell subsets to IL-7 stimulation, we have defined CD3+CD4+ T cells on the basis of CD45RA/RO and CD27 coexpression. Memory CD45RO+ T cells can be subcategorized into CD27+ and CD27− subsets. CD27− cells can be generated from prolonged stimulation of T lymphocytes [18]. Functionally, CD27+ memory T cells possess greater proliferative potential when activated by T cell receptor engagement than CD27− memory T cells [19, 20]. Memory CD4+CD45RA+ T cells are enriched for CD57+ terminally differentiated cells [21]. On the basis of this understanding of T cell maturation and functionality, we have examined phosphorylated STAT5 (STAT5-P) induction in CD4+CD3+ T cell subsets, including CD45RA+CD45RO− CD27+ (naive), CD45RA−CD45RO+CD27+ (CD27+ memory), CD45RA−CD45RO+CD27− (CD27− memory) and CD45RA+ CD45RO−CD27− (terminal memory) T cells. We found that these cell subsets have distinct responses to IL-7 stimulation as measured by STAT5-P induction, and we observed reduced responsiveness to IL-7 stimulation in cells from HIV-infected persons, especially memory T cells. These results have important implications for CD4+ T cell homeostasis during HIV disease.