T-cell immunoglobulin and mucin domain containing 4 (TIMD-4) also known as T-cell membrane protein 4 (TIM-4) is a protein in humans that is encoded by the TIMD4 gene.[5] TIM-4 genes are in mouse present on chromosome 11B1.1 and in humans on chromosome 5q33.2. TIM-4 contains IgV domain with integrin-binding site as well as a unique metal-ion-dependent ligand binding site for phosphatidylserine.[6] TIM-4 also contains mucin domain with high levels of O-glycosylation. In comparison to other TIM proteins (such as TIM-1, TIM-2...) it does not contain a tyrosine-phosphorylation motif in its intracellular tail domain.[7]
TIM-4 expression and function
Unlike other TIMs that are mainly expressed on T cells TIM-4 is expressed on APCs such as dendritic cells or macrophages.[7] TIM-4 serves as a ligand for TIM-1[8] but also as a receptor for phosphatidylserine. Its phosphatidylserine binding however does not mediate signalling instead it works more as a tethering receptor.[9] Its phosphatidylserine binding properties also play an important role in removal of apoptotic cells.[10] Moreover recognition of phosphatidylserine also helps to control adaptive immune system by clearing phosphatidylserine expressing apoptotic T cells. That leads to the regulation of antigen specific memory T cells.[11] TIM-4 is also able to inhibit naive T cells by non-TIM-1 receptor binding[12] but once T cells are active TIM-4 works as positive regulator helping to maintain their activity.[13][14] TIM-4 expression on macrophages plays an important role in their homeostatic maintenance.[15]
Role in diseases and possible clinical use
It was shown that TIM-4 plays a role in Th2 development. As such it plays a role in the development of allergies and might be a target for future therapies.[16][17] TIM-4 was also recognized as a factor in tumor development. For example it was shown that TIM-4 promotes colorectal cancer by activating angiogenesis and recruiting tumor associated macrophages.[18] TIM-4 also mediates autophagy at the site of tumor, which leads to reduced antigen presentation leading to increased toleration of tumor by the immune system.[19] Therefore there are studies using the blockade of TIM-4 as a complementary therapy for cancer treatment.[20]
^ abMeyers JH, Sabatos CA, Chakravarti S, Kuchroo VK (August 2005). "The TIM gene family regulates autoimmune and allergic diseases". Trends in Molecular Medicine. 11 (8): 362–9. doi:10.1016/j.molmed.2005.06.008. PMID16002337.
^Feng BS, Chen X, He SH, Zheng PY, Foster J, Xing Z, Bienenstock J, Yang PC (July 2008). "Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model". The Journal of Allergy and Clinical Immunology. 122 (1): 55–61, 61.e1–7. doi:10.1016/j.jaci.2008.04.036. PMID18547633.
^Tan X, Zhang Z, Yao H, Shen L (November 2018). "Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway". Cancer Letters. 436: 119–128. doi:10.1016/j.canlet.2018.08.012. PMID30118845. S2CID52031209.
^Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M (April 2013). "Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas". Cancer Immunology, Immunotherapy. 62 (4): 629–37. doi:10.1007/s00262-012-1371-9. PMID23143694. S2CID19381873.
