Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Abstract

IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection

“…In this study, the direct measurement of ex vivo spontaneous apoptotic cell death did not indicate any preferential apoptosis of CD4 ϩ CD127 ϩ T cells. Note, however, that this work has not ruled out a differential susceptibility of CD4 ϩ CD127 ϩ CD25 Ϫ T cells to Fas-mediated apoptosis, a possibility suggested by the observation that IL-7 increases susceptibility to Fas-mediated apoptosis (83). A further explanation for the loss of IL-7R␣ expression on CD4 ϩ T cells that is associated with HIV infection is that increased levels of circulating IL-7 result in active down-regulation of CD127 expression on a subset of CD4 ϩ T cells (37).…”

Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

“…Recent studies have indicated that IL-7 can promote Fasinduced T-cell apoptosis in nonactivated T cells [9]. At the same time, it can also increase Fas-mediated proliferative signals in suboptimally activated T cells [10], exerting a strong anti-apoptotic effect ex vivo on T cells from HIV-1-infected subjects [11].…”

Modelling the influence of activation-induced apoptosis of CD4 + and CD8 + T-cells on the immune system response of a HIV-infected patient

“…However, the role of interleukins on the immune system of HIV-infected patients/macaques is still a controversial issue since other studies (see e.g. [22]) have shown that they could have a detrimental effect. Nevertheless, these contradictory results concerning the effects of interleukins on the HIV infection could potentially be explained by the analysis of our extended model, which shows that a decrease in apoptosis rates does not necessarily lead to a better immune system response.…”