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

Benoit, Anitaa,d; Abdkader, Khaleda,d; Sirskyj, Danyloa,d; Alhetheel, Abdulkarima,d; Sant, Nadiaa,d; Diaz-Mitoma, Franciscoa,b,c,d; Kumar, Ashoka,b,c,d; Kryworuchko, Markoa,b,c,d

doi: 10.1097/QAD.0b013e32832b51be
Basic Science: Concise Communication

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-7Rαlow) 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-7Rαlow and IL-7Rαhigh 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-7Rαlow 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-7Rαlow 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.

aInfectious Disease and Vaccine Research Centre (IDVRC), Children's Hospital of Eastern Ontario (CHEO) – Research Institute, Canada

bDivision of Virology, Children's Hospital of Eastern Ontario, Canada

cDepartment of Pathology and Laboratory Medicine, University of Ottawa, Canada

dDepartment of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.

Received 26 September, 2008

Revised 12 February, 2009

Accepted 6 March, 2009

Correspondence to Dr Marko Kryworuchko, Infectious Disease and Vaccine Research Centre, Children's Hospital of Eastern Ontario – Research Institute, 401 Smyth Road, Ottawa, Ontario, K1H 8L1, Canada. Tel: +1 613 737 7600x2312; fax: +1 613 738 4869; e-mail: MKryworuchko@cheo.on.ca; mkryworu@uottawa.ca

© 2009 Lippincott Williams & Wilkins, Inc.