The role of IL-7 in lymphopenia and bystander apoptosis during HIV-1 infection

Abstract

The concentration of interleukin-7 (IL-7) in human serum is elevated in various clinical conditions associated with lymphopenia. IL-7 is an essential factor for T cell differentiation and survival, and high IL-7 concentration has been proposed to represent a homeostatic response to T cell depletion, which may accelerate thymic output and promote T cell regeneration. During HIV-1 infection, however, high levels of IL-7 are correlated with CD4+ T cell depletion and appear not to be beneficial to rescue the diminishing T cell pool.

In order to further understand the impact of T cell numbers on serum IL-7 levels at different clinical stages of HIV-1 infection we investigated specimens from HIV-1 infected patients during primary and chronic infection and in long term non-progressors (LTNPs). In patients with primary HIV-1 infection, CD4+ and CD8+ T cell counts showed no correlation with the high IL-7 levels found in these patients; however the significant association seen between IL-7 and total CD3+ T cell counts may reflect an effect of lymphopenia on the increased IL-7 level, as previously reported in chronic HIV-1 infection. We also studied IL-7 levels in LTNPs, characterized by CD4+ T cell counts above 500 cells/μl and control of viral replication for 7 to 10 years without ART. Some of the LTNPs individuals progressed to a symptomatic phase of HIV-1 infection and, interestingly, we observed that these individuals showed a higher IL-7 level before progression as compared to the LTNPs that maintained high CD4+ T cell counts and virological control.

We asked the question on whether positive effects of IL-7 on survival and homeostatic proliferation of T cells might be severely impaired in HIV-infected individuals due to IL-7Rα down-regulation. Thus the frequency of IL-7Rα- T cells in HIV-1 infected patients was studied in relation to CD4 Tcell counts, IL-7 concentration and expression in different T-cell populations. Down-regulation of IL-7Rα on T cells correlated with depletion of CD4 T cells (P < 0.001) and also with increased concentration of serum IL-7 (P < 0.05). Particularly, T cells with memory phenotype showed a decreased IL-7Rα expression in association with CD28 down-regulation. Thus, IL-7Rα downregulation and differentiation towards a CD28- memory phenotype in response to chronic activation may lead to an overall decrease of IL-7 mediated survival within the peripheral T-cell pool.

The loss of CD4+ T cells during HIV-1 infection is not entirely the cause of direct infection of these cells, but is also due to bystander apoptosis where uninfected cells are predisposed to death inducing signals. 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 showed that IL-7 up-regulates in vitro Fas expression on naïve and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. The role of IL-7 in Fas upregulation in vivo was verified in IL-7 treated macaques. In addition 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 that elevated IL-7 levels associated with HIV-1 infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

Alteration of receptor-mediated apoptosis is not limited to HIV-1 infection, but is also present in other infections including Leishmaniasis. Leishmaniasis infections often occur in areas of high HIV-1 prevalence. During Cutaneous Leishmaniasis (CL), caused by L. Major infection, there is a chronic inflammation process that leads to killing of the non-infected keratinocytes in the epidermis followed by disfiguring scar formations. Our studies showed that the expression of Fas, TRAIL-R2 and TRAIL is increased on keratinocytes upon exposure to supernatant from Leishmania infected PBMC cultures and in diseased skin from patients with CL. The expression of death receptors also renders the keratinocytes more sensitive to apoptosis and they can die through a bystander effect due to infiltrating immune cells expressing death ligands. Blocking Fas and TRAIL in vitro inhibits, to a great extent, apoptosis occurring in the experimental procedure.