Up-regulation of Tim-3 on T cells during acute simian immunodeficiency virus infection and on antigen specific responders.

Abstract

Understanding the role of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) on T cells and dendritic cells during the course of simian immunodeficiency virus (SIV) infection. Sequentially collected PBMCs from uninfected and SIVmac239-infected rhesus macaques were evaluated for Tim-3 expression by flow cytometry and antigen-specific responses. Blood innate immune cells (dendritic cells) and B cells showed high constitutive expression of Tim-3, whereas, compared to humans, only a minority of macaque T cells did. However, TIM-3 expression was transiently up-regulated on both CD4 and CD8 T cells during acute SIV infection, correlating with plasma viral loads, CD4 cell counts, and Ki67 expression up to 6 weeks postinfection and returned to baseline values by 8 weeks postinfection. Upon antigen-specific stimulation, most Tim-3 T cells produced various cytokines, suggesting that this marker is up-regulated on effector antigen-specific T cells and not associated with T-cell exhaustion. Among myeloid dendritic cells (mDCs), a clear separation was seen between blood mDCs expressing Tim-3 and those expressing PD-L2 - a ligand for inhibitory receptor programmed death 1. Rhesus macaques show constitutive expression of Tim-3 primarily on innate immune cells, but markedly lower levels on T cells compared to humans. Nevertheless, Tim-3 expression on T cells is transiently up-regulated during acute, but not chronic, SIV infection, and appears to be a marker of antigen-specific effector cells. The exact role and contribution of Tim-3 to the modulation of antiviral responses in vivo will require additional investigation.