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

Abstract

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.

PiggyBac Transposon-Mediated CD19 Chimeric Antigen Receptor-T Cells Derived From CD45RA-Positive Peripheral Blood Mononuclear Cells Possess Potent and Sustained Antileukemic Function

“…TIM-3 was initially identified as a molecule expressed by dysregulated, chronically-activated T cells and is generally considered to be a T-cell inhibitory protein (48,49). However, the recent studies have indicated that TIM-3 exerts paradoxical costimulatory effect on T cells, including enhancement of the phosphorylation of ribosomal S6 protein, which is present downstream of T-cell receptor signaling (50,51). We did not investigate the co-stimulatory function of TIM-3 on PB-CAR-T cells; however, based on the in vitro and in vivo potency of TIM-3 positive RA + CAR-T cells, the high expression of TIM-3 and LAG-3 on PB-CAR-T cell surface might not induce exhaustion which could impair the function of PB-CAR-T cells.…”

Tim-3 mediates T cell trogocytosis to limit antitumor immunity

“…MHC molecules acquired by trogocytosed antigen-specific T cells are cointernalized with TCRs through endocytosis and localized in endosomes and lysosomes. Our findings show that Tim-3, which is recruited to the immunological synapse upon T cell activation (39,40), plays a critical role in driving pMHC and membrane-associated protein transfer from Tim-3 + APCs to PS + activated T cells both in vitro and in melanoma-bearing mice, regulating T cell trogocytosis and fratricide killing.…”

Novel Genes Potentially Involved in Fibroblasts of Diabetic Wound

“…Three subfamilies were found in the MAPK signaling pathway, including the extracellular-signal-regulated kinases (ERK MAPK, Ras/Raf1/MEK/ERK), the c-Jun N-terminal or stress-activated protein kinases (JNK, SAPK), and p38 [ 16 – 18 ]. Once the pathway was activated, a number of downstream target kinases including MAPKAPK3 could be activated [ 19 ]. Recently, some researchers have fabricated an in situ injectable hydrogel which can markedly accelerate diabetic wound healing through activating the TGF- β /MEK/MAPK signaling pathway [ 20 ].…”