Research ArticleT CELL SIGNALING

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

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Science Signaling  15 Jun 2021:
Vol. 14, Issue 687, eaba0717
DOI: 10.1126/scisignal.aba0717

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Stimulating under the right conditions

Because the transmembrane receptor Tim-3 is increased in abundance on exhausted T cells, it is thought to inhibit T cell activation and is being considered as a therapeutic target to reinvigorate antitumor responses. Kataoka et al. used imaging techniques to demonstrate the recruitment of Tim-3 to the immune synapses of T cells in contact with antigen-presenting cells. This recruitment required the transmembrane (TM) domain of Tim-3 and led to enhanced signaling downstream of the T cell receptor (TCR). A chimeric antigen receptor incorporating the Tim-3 TM domain also provided activating signals, suggesting that Tim-3 can act as a costimulator of TCR signaling under certain conditions.


Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

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