Besides this, investigation into this malignancy due to high immune checkpoint expression and the change of immunometabolic programming in immune cells and tumor cells is highly considered. to suppress immune responses. Open in a separate window Physique 1 TIM-3, its ligands, and PK11007 signal transduction events. Gal-9, PtdSer, CEACAM1, and HMGB-1 are the most important ligands for TIM-3. HMGB1 can bind to TIM-3 expressed on APCs and suppress innate immune responses. PtdSer and TIM-3 conversation leads to an increase in the phagocytosis of apoptotic cells (A). Binding of TIM-3 to Gal-9 and other TIM-3 ligands leads to phosphorylation of Y256 and Y263 by the tyrosine kinase ITK or Fyn and release of Bat3 from the TIM-3 tail, which promotes TIM-3-mediated T cell inhibition (B). When TIM-3 is not bound by a ligand, Bat3 links to the C-terminal tail of TIM-3 (the Tyr 256 and Tyr 263 in the C-terminal tail) and blocks SH2 domain-binding sites in its tail and recruits the active catalytic form of LCK that promotes T cell signaling (C). Bat3, HLA-B associated transcript 3; CEACAM1, carcinoembryonic antigen cell adhesion molecule 1; Gal-9, galectin-9; HMGB-1, high-mobility group protein 1. The TIM-3 PK11007 expressed on monocytes, macrophages, and DCs acts as a phagocytic receptor for apoptotic cells and enhances the phagocytosis of apoptotic cells conversation with PtdSer, thereby boosting antigen cross-presentation (Physique 1A) (19). The biological relationship between the TIM-3 and PtdSer in T cells is usually unknown as T cells do not have a role in removing apoptotic bodies, but it seems that the conversation of TIM-3 with PtdSer can be effective in the production of IL-10 by T cells because IL-10 has been demonstrated to be expressed by TIM-3+ T cells (Physique 1B) (20). The HMGB1 as a damage-associated molecular pattern (DAMP) that binds to DNA released from dying cells boosts nucleic acid sensing by toll-like receptors (TLRs), but during chronic contamination and cancers, due to HMGB1 binding to TIM-3 expressed on APCs, Rabbit polyclonal to IP04 it seems that this conversation suppresses innate immune responses to the nucleic acid (Physique 1A) (13, 21). CEACAM1 is usually another newly identified ligand for TIM-3 that is co-expressed with TIM-3 in T cells and also is expressed by DCs and other APCs (Physique 1B). Therefore, the TIM-3 and CEACAM1 form an axis that can inhibit immune responses either in cis or trans T cells and myeloid cells, thereby downregulating their antitumor immunity. The stability of mature TIM-3 around the cell surface is promoted cis conversation, and both cis and trans interactions mediate the inhibitory function of TIM-3 (16, 22). Signal Transduction Events of TIM-3 In contrast to other co-stimulatory and co-inhibitory molecules on immune cells, TIM-3 does not have a classical immunoreceptor tyrosine-based inhibition (ITIM) or immunoreceptor tyrosine-based switch (ITSM) motif in its cytoplasmic tail; however, it contains five tyrosine residues that are conserved between humans and mice. In humans, phosphorylation of two of the PK11007 tyrosine residues, Y265 and Y272 (Y256 and Y263 in mice), has been shown to be critically important for triggering downstream signaling pathways. Van de Weyer et al. exhibited that Y265 of human TIM-3 is specifically phosphorylated by the enzyme interleukin inducible T cell kinase (ITK) from the TEC family of kinases when TIM-3 has an conversation with Gal-9 (23). Another study using the Jurkat, D10, and HEK293T cell lines, has shown that this Src family of kinases, Fyn and Lck, can phosphorylate a TIM-3 cytoplasmic portion (15, 24). Intriguingly, evidence suggests that TIM-3 may act as a constitutive positive regulator of T cell function and enhance signaling pathways that lead to T cell activation, at least under conditions of acute stimulation. J. Lee et al. reported that this recruitment of SH2 domain-containing proteins, including the p85 of PI3K and PLC-1 to the phosphorylated tail of TIM-3 in the Jurkat T cell line stimulated by TCR/CD3 and PK11007 CD28, enhances the secretion of IL-2 and the induction of transcription factors important for T-cell activation, i.e., NFAT, AP-1, and NF-kB conversation of the components of the TCR signaling pathway,.