Acute stimulation generates Tim-3-expressing T helper type 1 CD4 T cells that persist in vivo and show enhanced effector function

Abstract

T-cell immunoglobulin and mucin domain 3 (Tim-3) is a surface receptor expressed by T helper type 1 (Th1) effector CD4 T cells, which are critical for defence against intracellular pathogens and have been implicated in autoimmune disease. Previous studies showed that Tim-3 expression makes Th1 cells more susceptible to apoptosis and also marks functionally impaired T cells that arise due to chronic stimulation. However, other studies suggested that Tim-3-expressing Th1 cells do not always have these properties. To further define the relationship between Tim-3 and Th1 cell function, we analysed the characteristics of Th1 cells that expressed Tim-3 in response to brief stimulation in vitro or an acute viral infection in vivo. As expected, cultured CD4 T cells began expressing Tim-3 during Th1 differentiation and secondary stimulation generated Tim-3− and Tim-3+ fractions that were separated and further analysed. When injected into naive mice, Tim-3+ cells down-regulated Tim-3 and survived equally well compared with Tim-3- cells. Further, Tim-3− and Tim-3+ Th1 cells had similar functional responses when transferred into naive mice that were subsequently infected with lymphocytic choriomeningitis virus (LCMV). Cultured Th1 cells that expressed Tim-3 following T-cell receptor stimulation had a greater capacity to express signature Th1 cytokines than their Tim-3− counterparts and showed differential expression of genes that regulate CD4 T-cell function. Consistent with these findings, Tim-3+ Th1 cells generated in response to LCMV infection displayed augmented effector function relative to Tim-3− cells. These results suggest that Tim-3 expression by Th1 cells responding to acute stimulation can mark cells that are functionally competent and have an augmented ability to produce cytokines.