Inflammatory cytokines drive CD4+ t-cell cycling and impaired responsiveness to interleukin 7: Implications for immune failure in HIV disease

Carey L. Shive, Joseph C. Mudd, Nicholas T. Funderburg, Scott F. Sieg, Benjamin Kyi, Doug A. Bazdar, Davide Mangioni, Andrea Gori, Jeffrey M. Jacobson, Ari D. Brooks, Jeffrey Hardacre, John Ammori, Jacob D. Estes, Timothy W. Schacker, Benigno Rodriguez, Michael M. Lederman

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Background. Systemic inflammation has been linked to a failure to normalize CD4+ T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure. Methods. We examined the in vitro effects of IL-6 and interleukin 1β (IL-1β) on peripheral blood T-cell cycling and CD127 surface expression. Results. The proinflammatory cytokine IL-1β induces cell cycling and turnover of memory CD4+ T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1β and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor α chain (IL-7Rα). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1β attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin α4β7. We found elevated expression of IL-1β in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy. Conclusions. Induction of CD4+ T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4+ T-cell reconstitution in treated HIV-infected subjects.

Original languageEnglish (US)
Pages (from-to)619-629
Number of pages11
JournalJournal of Infectious Diseases
Volume210
Issue number4
DOIs
StatePublished - Aug 15 2014

Keywords

  • HIV
  • Immune failure
  • Inflammation
  • Interleukin 1 beta
  • Interleukin 6
  • Interleukin 7

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Shive, C. L., Mudd, J. C., Funderburg, N. T., Sieg, S. F., Kyi, B., Bazdar, D. A., Mangioni, D., Gori, A., Jacobson, J. M., Brooks, A. D., Hardacre, J., Ammori, J., Estes, J. D., Schacker, T. W., Rodriguez, B., & Lederman, M. M. (2014). Inflammatory cytokines drive CD4+ t-cell cycling and impaired responsiveness to interleukin 7: Implications for immune failure in HIV disease. Journal of Infectious Diseases, 210(4), 619-629. https://doi.org/10.1093/infdis/jiu125