Abstract

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.

Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, Hecht TT, Hill BJ, Komschlies K, Tomaszewski J, Franchini G, Mackall CL. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates.
Blood
.
2003
;
101
(6):
2294
–9.
Nugeyre MT, Monceaux V, Beq S, Cumont MC, Ho Tsong Fang R, Chene L, Morre M, Barre-Sinoussi F, Hurtrel B, Israel N. IL-7 stimulates T cell renewal without increasing viral replication in simian immunodeficiency virus-infected macaques.
J Immunol
.
2003
;
171
(8):
4447
–53.

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