TY - JOUR TI - The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse AU - Kataoka, Shunsuke AU - Manandhar, Priyanka AU - Lee, Judong AU - Workman, Creg J. AU - Banerjee, Hridesh AU - Szymczak-Workman, Andrea L. AU - Kvorjak, Michael AU - Lohmueller, Jason AU - Kane, Lawrence P. T2 - Science Signaling AB -

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.

DA - 2021/06/15/ PY - 2021 DO - 10.1126/scisignal.aba0717 DP - stke.sciencemag.org VL - 14 IS - 687 J2 - Sci. Signal. LA - en SN - 1945-0877, 1937-9145 UR - https://stke.sciencemag.org/content/14/687/eaba0717 Y2 - 2021/06/16/16:50:08 ER -