| Author |
Sacha, Jonah B. Hansen, Scott G. Ndhlovu, Lishomwa C. Ishii, Naoto Kuroda, Marcelo J. Chew, Glen M. Rini, James M. Fujita, Tsuyoshi Burwitz, Benjamin J. Reed, Jason S. Ostrowski, Mario A. Clayton, Kiera L. Pathak, Reesab Seger, Elizabeth |
| Description |
Author Affiliation: Fujita T ( Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813); Burwitz BJ ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Chew GM ( Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813); Reed JS ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Pathak R ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Seger E ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Clayton KL ( Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada); Rini JM ( Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada); Ostrowski MA ( Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada); Ishii N ( Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Kuroda MJ ( Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433.); Hansen SG ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Sacha JB ( Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006); Ndhlovu LC ( Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813) |
| 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. |
