Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection

Abstract

Background HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naïve T cell numbers, elevated T cell turnover, senescence and inflammation. Methods Blood samples from immune failures (n=60), immune successes (n=20) and healthy controls (n=20) were examined for plasma IL-7 levels, for cellular expression of the IL-7Rα chain (CD127), for the exhaustion and senescence markers PD-1 and CD57, and for the survival factor Bcl2. As both inflammatory and homeostatic cytokines can induce T cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers. Results Plasma levels of IL-7 were elevated and both CD4 and CD8 T cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naïve CD4 T cell counts in immune success and inversely with T cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, while the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory (IL-1β) or homeostatic (IL-7) cytokines. Conclusions Perturbation of the IL-7/IL-7 receptor axis, increased T cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients.

Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery

“…Consistent with previous observations [18], we found that CD127 expression was diminished in T cells from IF subjects and other studies indicate that IL-7 is increased in plasma of IF subjects [26]. It is possible, therefore, that reduced CD127 expression is a consequence of increased chronic exposure of T cells to high concentrations of IL-7 in vivo leading to IL-7 hyporesponsiveness.…”

“…IL-7 induced Akt phosphorylation (P-Akt) is linked to cell cycle progression and T cell proliferation [15, 16]. Plasma IL-7 levels in IF patients are increased when compared to IL-7 levels in patients who recovered CD4 T cells [17]. In contrast, the capacity of CD4 T cells to respond to IL-7 stimulation as measured by rapid induction of P-STAT5 is diminished in IF patients and associated with reduced expression of CD127 [18].…”

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

“…In contrast, they found positive associations between baseline CD127 density on CD4 + T cells and an increase in CD4 + RTE cell counts and naïve CD4 + T‐cell counts after 2 years of effective ART, indicating that CD127 expression on CD4 + T cells is a predictor of increased thymic output after 2 years of suppressive ART . Furthermore, a few studies have found that in INRs, plasma levels of IL‐7 were elevated and CD127 expression both on CD4 + and CD8 + T cells was decreased; however, there was no statistically significant correlation between the baseline plasma IL‐7 level and absolute CD4 + T‐cell count after successful ART . Furthermore, others have shown a positive association or a negative association between baseline plasma IL‐7 levels and CD4 recovery in HIV‐1‐infected individuals after ART initiation.…”

Immune checkpoint blockade in infectious diseases

“…In the absence of ART, increased expression of PD-1 was associated with accelerated decline in CD4 + T cells following acute infection 48 and untreated chronic infection 36 . Following ART, PD-1 expression on CD8 + T cells has been associated with impaired CD4 + T cell immune reconstitution 49 microvascular disease 50 , elevated oxidised high and low density lipoproteins 51 and a shorter time to viral rebound once ART was stopped 52 .…”