Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1

A. E. Hogg, G. C. Bowick, N. K. Herzog, M. W. Cloyd, Janice Endsley

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Immunosuppression following infection with HIV-1 pre-disposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb. Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood. Using primary human CD8+ T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8+ CD45RO+ T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8+ T cells. We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8+ T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21. Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8+ T cells. These results suggest that HIV-1 infection of PBMC may reduce the antimicrobial profile of activated CD8+ T cells by disrupting signaling events that are critical for the induction of granulysin. Understanding the effects of HIV-1 on CD8+ T cell activation is essential to understanding the physiological basis for inadequate cytotoxic lymphocyte activity in HIV + patients and for informed guidance of cytokine-based therapy to restore T cell function.

Original languageEnglish (US)
Pages (from-to)1191-1203
Number of pages13
JournalJournal of Leukocyte Biology
Volume86
Issue number5
DOIs
StatePublished - Nov 2009

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Interleukin-15
HIV-1
T-Lymphocytes
HIV Infections
interleukin-21
Immunosuppressive Agents
Infection
Natural Killer Cells
Immunosuppression
Tissue Donors
HIV
Lymphocytes
Cytokines

Keywords

  • Cytokines
  • Cytotoxicity
  • Human
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

Cite this

Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1. / Hogg, A. E.; Bowick, G. C.; Herzog, N. K.; Cloyd, M. W.; Endsley, Janice.

In: Journal of Leukocyte Biology, Vol. 86, No. 5, 11.2009, p. 1191-1203.

Research output: Contribution to journalArticle

Hogg, A. E. ; Bowick, G. C. ; Herzog, N. K. ; Cloyd, M. W. ; Endsley, Janice. / Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1. In: Journal of Leukocyte Biology. 2009 ; Vol. 86, No. 5. pp. 1191-1203.
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AB - Immunosuppression following infection with HIV-1 pre-disposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb. Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood. Using primary human CD8+ T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8+ CD45RO+ T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8+ T cells. We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8+ T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21. Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8+ T cells. These results suggest that HIV-1 infection of PBMC may reduce the antimicrobial profile of activated CD8+ T cells by disrupting signaling events that are critical for the induction of granulysin. Understanding the effects of HIV-1 on CD8+ T cell activation is essential to understanding the physiological basis for inadequate cytotoxic lymphocyte activity in HIV + patients and for informed guidance of cytokine-based therapy to restore T cell function.

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