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

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5576-5583
Number of pages8
JournalJournal of Immunology
Volume193
Issue number11
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Fujita, T., Burwitz, B. J., Chew, G. M., Reed, J. S., Pathak, R., Seger, E., Clayton, K. L., Rini, J. M., Ostrowski, M. A., Ishii, N., Kuroda, M. J., Hansen, S. G., Sacha, J. B., & Ndhlovu, L. C. (2014). Expansion of dysfunctional Tim-3 - Expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. Journal of Immunology, 193(11), 5576-5583. https://doi.org/10.4049/jimmunol.1400961