IL-7 Differentially Regulates Cell Cycle Entry and Exit of Naive and Memory CD4+ T Lymphocytes: Effects on HIV-Mediated Infection.

The IL-7 cytokine plays a major role in the in vivo maintenance of polyclonal naive and memory T-cells, positively regulating the survival, differentiation and proliferation of thymocyte and peripheral T lymphocyte populations. Under conditions of lymphopenia due to HIV infection, it has been shown that increased peripheral IL-7 levels correlate with T cell differentiation. Moreover, a short-term exogenous IL-7 treatment enhances T-cell differentiation as well as expansion of naive and memory T-cells. These properties have lead to the proposal that recombinant IL-7 be used as an adjuvant immune therapy in HIV-infected individuals. Nevertheless, primate studies have shown that after an initial increase in in vivo T cell proliferation, there is a substantial drop in the absolute lymphocyte numbers (Fry et al., 2003; Nugeyre et al., 2003). As the bases for this decrease have not yet been elucidated, it is important to assess the long-term biological effects of IL-7 on quiescent human CD4+ T lymphocyte subsets. Here, we demonstrated that although IL-7-stimulated memory T-cells enter into cycle much more rapidly than their naive counterpart (3 days as compared to 6 days), they also exit the cell cycle much earlier, by day 10 vs. day 18. Importantly, cell cycle exit occurred despite the continuous replenishment of IL-7 and was inversely correlated with IL-7 receptor levels. Specifically, IL-7Rα levels were completely downregulated on both naive and memory T subsets within 12 hours post cytokine treatment but were significantly re-upregulated in memory T cell within 8–10 days. In naive lymphocytes, IL7Rα expression was absent during the first 14 days of continuous IL-7 stimulation after which time it slowly increased, with expression coinciding with cell cycle exit. Importantly, the permissivity of IL-7-stimulated CD4+ lymphocytes to infection with an HIV-1 vector was not related to cell cycle entry per se. After extended IL-7 stimulation of the naive T cell subset, they remained more refractory to HIV-1 vector infection than memory cells even though they demonstrated a higher level of cell cycle progression. Moreover, under conditions mimicking the lymph node environment, cell cycle entry was not required for IL-7 mediated infection. The differential effects of recombinant IL-7 on the cell cycle entry-exit status of naive and memory CD4+ T lymphocytes as well as the relative susceptibilities of these CD4+ subsets to HIV-1 vector infection have important implications for the use of this cytokine as an adjuvant immunotherapy.