Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques

Tsuyoshi Fujita, Benjamin J. Burwitz, Glen M. Chew, Jason S. Reed, Reesab Pathak, Elizabeth Seger, Kiera L. Clayton, James M. Rini, Mario A. Ostrowski, Naoto Ishii, Marcelo J. Kuroda, Scott G. Hansen, Jonah B. Sacha, Lishomwa C. Ndhlovu

研究成果: Article査読

18 被引用数 (Scopus)

抄録

The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8+ T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8+ T cell responses in vitro, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3+CD8+ T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3+PD-1+CD8+ T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8+ T cells in all tissues examined. Tim-3+CD8+ T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3-CD8+ T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8+ T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8+ T cell responses.

本文言語English
ページ(範囲)5576-5583
ページ数8
ジャーナルJournal of Immunology
193
11
DOI
出版ステータスPublished - 2014 12 1

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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