Regulatory Dysfunction of the Interleukin-7 Receptor in CD4 and CD8 Lymphocytes From HIV-Infected Patients-Effects of Antiretroviral Therapy

Abstract

Despite an increase in plasma IL-7 levels, the CD4 T-cell pool decrease progressively in HIV-infected patients. Here we report on our tests to check the hypothesis that defects in the IL-7 receptor system might be involved in this phenomenon. The cell surface expression of CD127 was measured ex vivo in CD4 and CD8 T lymphocytes drawn from 3 groups of HIV patients. IL-7 function was also followed in vitro by measuring IL-7-driven T-cell proliferation, the induction of the CD25 activation marker, and overexpression of the antiapoptotic molecule Bcl-2. Untreated viremic patients showed a slight but significant decrease in CD127 expression on the surface of their CD4 lymphocytes. By contrast, CD127 expression was substantially altered on the surface of CD8 T lymphocytes taken from untreated viremic patients. IL-7-induced overexpression of the antiapoptotic molecule Bcl-2 was dramatically altered in viremic patients, whereas IL-7-dependent CD25 induction and T-cell proliferation were reduced. Highly active antiretroviral therapy partially corrected these defects in patients with an undetectable viral load and CD4 counts of more than 400 cells/microL. The effects of HAART were less pronounced in patients with undetectable VL but low CD4 counts (<250 cells/microL). The IL-7 receptor is dysfunctional in the CD4 and CD8 lymphocytes of HIV-infected patients. This may be due to abnormal activation of the immune system in HIV-infected patients and may contribute to the reduced CD4 count and the altered function of the CD8 compartment.

Elevated IFN-alpha/beta levels in a streptozotocin-induced type I diabetic mouse model promote oxidative stress and mediate depletion of spleen-homing CD8+ T cells by apoptosis through impaired CCL21/CCR7 axis and IL-7/CD127 signaling

“…Despite decrease in IL-7, CD8+ T cells response becomes progressively impaired within diabetes, suggesting an inability of CD8+ T cells to respond to IL-7. Impaired CD8+ T cell function and decreased CD127 expression have recently been linked to abnormal activation of the immune system and are contributed to immunodeficiency [76]. A recent study confirmed that removing CD127 (IL-7R α) from the cell surface leads to an HIV Tat protein mediated-reduction of IL-7 signaling and impairs CD8 T cell proliferation and function [77], which we similarly observed, as shown in Figures 4 and 5A.…”

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

“…1a; p=0.05). Earlier studies found decreased T cell expression of CD127 associated with low CD4 T cell numbers [11, 13, 23-25]. We found a significant reduction in CD127 density on CD4 T cells from both immune success and immune failure patients when compared to CD127 density among healthy controls (p=0.03; p=0.0005 respectively), but there was no difference between CD127 density in immune failure and immune success (p=0.25) (Fig.…”

“…In earlier work, we and others found that these immune failure patients had decreased numbers of both CD4 and CD8 naïve T cells, increased activation of CD4 and CD8 T cells as measured by HLADR and CD38 expression, increased cycling of CD4 memory T cells as measured by Ki67 expression, and elevated plasma indices of inflammation and coagulation[7-10]. Immune failure patients may also have perturbations of immune homeostasis as T cell expression of the IL-7 receptor alpha chain (CD127) is diminished [11-13], and there is increased T cell expression of the immune senescence and exhaustion markers, CD57 and PD-1 [14-17]. Recovery of CD4 T cells may be impaired at many stages; naïve T cells may be less responsive to homeostatic signals, mature T cells may display increased turnover or increased sensitivity to death signals and more matured T cells may show signs of exhaustion and senescence.…”

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+and CD8+T cells from HIV-1-infected individuals

“…The rate of CD4 ϩ T cell destruction in patients with advanced HIV-1 disease may exceed the regenerative capacity of IL-7 or the pool of progenitor T cells may be irreversibly damaged or depleted. Alternatively, the IL-7/IL-7 receptor axis may be impaired (37). The marked sensitivity to the effects of IL-7 that we documented in patients with low CD4 ϩ T cell counts indicates that circulating T cells from these patients did express a functional IL-7 receptor.…”

“…Increased plasma levels of IL-7 were documented in HIV-1-infected individuals and inversely correlated with CD4 counts (30,31,36). In parallel, the expression of the ␣-chain of the IL-7 receptor (CD127) was shown to be downmodulated (24,36,37). Because the levels of IL-7 decreased when the CD4 ϩ T cell counts were restored during therapy, the increases in IL-7 levels have been interpreted as a homeostatic response to lymphopenia (31).…”