T cell Immunoglobulin and Mucin domain 3 (TIM-3) is an Ig superfamily member expressed on IFNγ-secreting Th1 and Tc1 cells identified as a negative regulator of immune tolerance. TIM-3 is expressed by a subset of activated CD4+ T cells, and anti-CD3/anti-CD28 stimulation increases both the level of expression and the number of TIM-3+ T cells. In mice, TIM-3 is constitutively expressed on natural regulatory T cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4+ T cell differentiation. Here, we examined TIM-3 expression on human Tregs to determine its role in T cell suppression. In contrast to mice, TIM-3 is not expressed on Tregs ex vivo but is upregulated after activation. While TIM-3+ Tregs with increased gene expression of lag3, ctla4 and foxp3 are highly efficient suppressors of effector T cells (Teff), TIM-3— Tregs poorly suppressed Th17 as compared to Th1 cells that was associated with decreased STAT-3 expression and phosphorylation with reduced gene expression of il10, ebi3, gzmB, prf1, il1Rα, and ccr6. Thus, our results suggest that TIM-3 expression on Tregs identifies a population highly effective in inhibiting pathogenic Th1 and Th17 responses.

Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.