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


OBJECTIVE
To evaluate cytokine-induced STAT activation in IL-7Ralpha(low) and IL-7Ralpha(high) CD8 T cells from chronically infected HIV-positive patients and investigate the potential molecular mechanism involved in the reduced IL-7Ralpha 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-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.
Benoit
Anita
A
Infectious Disease and Vaccine Research Centre, Children's Hospital of Eastern Ontario - Research Institute, Ottawa, Canada.
Abdkader
Khaled
K
Sirskyj
Danylo
D
Alhetheel
Abdulkarim
A
Sant
Nadia
N
Diaz-Mitoma
Francisco
F
Kumar
Ashok
A
Kryworuchko
Marko
M
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic
D016207:Cytokines; D018121:Receptors, Cytokine