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

BACKGROUND:: CD8 T lymphocytes from chronically infected HIV-positive patients degenerate into a preapoptotic state and exhibit impaired functionality. Particularly in viremic patients, this was associated with an increased proportion of interleukin-7 receptor-α low-expressing (IL-7Rα) effector-like CD8 T cells. As cytokine signaling through signal transducers and activators of transcription (STAT) is essential for cellular function, we hypothesized that activation of this pathway may be impaired in these cells. OBJECTIVES:: To evaluate cytokine-induced STAT activation in IL-7Rα and IL-7Rα CD8 T cells from chronically infected HIV-positive patients and investigate the potential molecular mechanism involved in the reduced IL-7Rα expression. METHODS:: CD8 T cells from HIV-positive patients on and off antiretroviral therapy were assayed respectively for STAT activation, cytokine receptor, and transcription factor expression by flow cytometry and real-time PCR. RESULTS:: IL-7 stimulation failed to activate STAT5 in a substantial proportion of patient CD8 T cells. This correlated with reduced IL-7Rα mRNA and surface protein expression. Interestingly, IL-7Rα 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-7Rα transcriptional repressor, but not that of other transcriptional regulators studied, including Gfi-1B and GA-binding protein α. Programmed death-1 inhibitory receptor, though upregulated in CD8 T cells from HIV-positive patients, appeared unrelated to IL-7Rα expression and STAT signaling capacity. CONCLUSION:: IL-7Rα CD8 T lymphocytes remain responsive to cytokines important in their homeostasis at the level of STAT signaling other than IL-7, and results suggest an IL-7Rα transcriptional repression mechanism involving Gfi-1. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.