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

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.