Inverse association of repressor growth factor independent-1 with CD8 T cell interleukin (IL)-7 receptor α expression and limited signal transducers and activators of transcription signaling in response to IL-7 among γ-chain cytokines in HIV patients

Abstract

IL-7 stimulation failed to activate STAT5 in a substantial proportion of patient CD8 T cells. This correlated with reduced IL-7Ralpha mRNA and surface protein expression. Interestingly, IL-7Ralpha(low) cells appeared to be fully capable of recruiting the STAT pathway in response to IL-2, IL-4, IL-10, and IL-15. mRNA expression suggested a potential role for growth factor independent (Gfi)-1 as an IL-7Ralpha transcriptional repressor, but not that of other transcriptional regulators studied, including Gfi-1B and GA-binding protein alpha. Programmed death-1 inhibitory receptor, though upregulated in CD8 T cells from HIV-positive patients, appeared unrelated to IL-7Ralpha expression and STAT signaling capacity.

HIV infection of thymocytes inhibits IL-7 activity without altering CD127 expression

“…The regulation of CD127 by HIV may play a role in disease pathogenesis since the expression of CD127 has been correlated with measures of disease progression (decreased CD4 count, increased viral load, increased immune activation) [24,25]. In addition to decreased CD127 expression on T-cells, we and others have also shown that CD127 signalling is impaired in HIV infection [26-28]. Given the importance of the role of IL-7 in HIV pathogenesis and the current development of IL-7 as a therapeutic agent for HIV infection and other conditions, understanding the mechanism by which HIV impairs IL-7 activity within the thymus is of the greatest importance.…”

“…While in vitro HIV infection did not affect surface CD127 expression on thymocytes, it remains possible that in vitro HIV infection is associated with altered IL-7 signalling as has been reported in CD8 + T-cells from HIV-infected individuals [26-28]. This was, therefore, evaluated by measuring IL-7 responsiveness of thymocytes following HIV infection.…”

Dual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 Pathway

“…ϩ T-cell subset of viremic patients with high levels of chronic immune activation, which may account for the perturbed IL-7 responses observed in this subset (11,22,41,49,54,60). However, it should be noted that decreased CD127 expression may be compensated for by increased ␥c expression and that the net effect of these changes on IL-7 binding capacity has not been investigated so far.…”

Decreased IL-7 Responsiveness Is Related to Oxidative Stress in HIV Disease

“…It is plausible that diminished IL-7 receptor expression (CD127) is a key determinant of reduced IL-7 responsiveness in HIV disease. In support of this possibility, some studies have found a tight correlation between IL-7-induced P-STAT5 signaling and CD127 expression, particularly among CD8 cells [11]. Nonetheless, isolated CD8+CD127+ cells from HIV+ donors have defects in P-STAT5 signaling [13].…”

“…The IL-7/IL-7 receptor axis is perturbed in HIV disease such that serum levels of IL-7 cytokine are increased [4] while T cell expression of IL-7 receptor is diminished [5], [6], [7], [8], [9], [10]. T cells from HIV-infected persons also tend to display poor intracellular signaling responses to IL-7 stimulation, particularly as measured by phosphorylation of STAT-5 [5], [11], [12], [13]. These perturbations in IL-7 responsiveness could contribute to HIV pathogenesis and adversely affect T cell reconstitution during administration of anti-retroviral therapy.…”