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J Immunol. 2014 Dec 1;193(11):5576-83. doi: 10.4049/jimmunol.1400961. Epub 2014 Oct 27.

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

Author information

1
Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813; Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
2
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
3
Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813;
4
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
5
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
6
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433.
7
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006; lndhlovu@hawaii.edu sacha@ohsu.edu.
8
Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813; lndhlovu@hawaii.edu sacha@ohsu.edu.

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 and, 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.

PMID:
25348621
PMCID:
PMC4239185
DOI:
10.4049/jimmunol.1400961
[Indexed for MEDLINE]
Free PMC Article

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