Expansion of Dysfunctional Tim-3 Expressing Effector Memory CD8+ T cells during SIV Infection in Rhesus Macaques

The T cell immunoglobulin- and mucin domain-containing molecule (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 anti-viral 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 here 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 to Tim-3 − CD8 + T cells. During acute phase SIV replication Tim-3 expression peaked on SIV-specific CD8 + T cells by 2 weeks post infection, and then rapidly diminished irrespective of mutational escape of cognate antigen, 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.