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.

Immune regulation by Tim-3

“…Furthermore, the absence of Tim-3 leads to defective Akt/mTOR signaling 23 ; however, in the chronic LCMV T-cell exhaustion model, Tim-3 expression was sufficient to dampen the anti-PD-1 rescue of T-cell responses, thereby suggesting crosstalk of PD-1 and Tim-3 in exhausted T cells 23 , as discussed above. Supporting this finding is the recent report by Gorman and Colgan that acute stimulation in response to LCMV infection leads to upregulation of Tim-3 in persisting Th1-type CD4 cells, and these cells also show enhanced effector functions both in vitro and in vivo 24 .…”

Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

“…Previous research has established inhibitory receptors to play a critical role in T cell exhaustion in chronic infections after prolonged antigen exposure (14,15,42,43). However, inhibitory receptors also have important functions and are transiently expressed during acute infections (17,24,(44)(45)(46)). Many studies have described an increased expression of inhibitory receptors on both CD8 + and CD4 + T cells during malaria infection (26,27,47,48).…”

Effect of pembrolizumab on CD4+CD25+, CD4+LAP+ and CD4+TIM-3+ T cell subsets

“…Lack of FoxP3 expression after early activation in TIM-3 + cells suggested that these cells are non-suppressive and could be effector cells. Gorman and Colgan showed that, following stimulation, Th1 cells express TIM-3 and release more cytokines than TIM-3cells [17]. These proliferating TIM-3 + T cells are functionally competent and have an amplified ability to produce cytokines such as IL-2, that serves as an autocrine growth factor, that result in increased proliferation of responder T cells.…”