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-alpha low-expressing (IL-7R alpha(low)) 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-7R alpha(low) and IL-7R alpha(high) CD8 T cells from chronically infected HIV-positive patients and investigate the potential molecular mechanism involved in the reduced IL-7R alpha 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-7R alpha mRNA and surface protein expression. Interestingly, IL-7R alpha(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-7R alpha transcriptional repressor, but not that of other transcriptional regulators studied, including Gfi-1B and GA-binding protein a. Programmed death-1 inhibitory receptor, though upregulated in CD8 T cells from HIV-positive patients, appeared unrelated to IL-7R alpha expression and STAT signaling capacity.
Conclusion: IL-7R alpha(low) 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-7R alpha transcriptional repression mechanism involving Gfi-1. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins