TIMD4

Unlike other TIMs that are mainly expressed on T cells TIM-4 is expressed on APCs such as dendritic cells or macrophages. TIM-4 serves as a ligand for TIM-1{{cite journal | title = Dogmas, paradigms and proving hypotheses | journal = Nature Immunology | volume = 11 | issue = 6 | pages = 455 | date = June 2010 | pmid = 20485268 | doi = 10.1038/ni0610-455 | doi-access = free }} but also as a receptor for phosphatidylserine. Its phosphatidylserine binding however does not mediate signalling instead it works more as a tethering receptor.{{cite journal | vauthors = Park D, Hochreiter-Hufford A, Ravichandran KS | title = The phosphatidylserine receptor TIM-4 does not mediate direct signaling | journal = Current Biology | volume = 19 | issue = 4 | pages = 346–51 | date = February 2009 | pmid = 19217291 | doi = 10.1016/j.cub.2009.01.042 | s2cid = 17015987 | doi-access = free }} Its phosphatidylserine binding properties also play an important role in removal of apoptotic cells.{{cite journal | vauthors = Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ | title = TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells | journal = Immunity | volume = 27 | issue = 6 | pages = 927–40 | date = December 2007 | pmid = 18082433 | pmc = 2757006 | doi = 10.1016/j.immuni.2007.11.011 }} 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.{{cite journal | vauthors = Albacker LA, Karisola P, Chang YJ, Umetsu SE, Zhou M, Akbari O, Kobayashi N, Baumgarth N, Freeman GJ, Umetsu DT, DeKruyff RH | title = TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells | journal = Journal of Immunology | volume = 185 | issue = 11 | pages = 6839–49 | date = December 2010 | pmid = 21037090 | pmc = 3153437 | doi = 10.4049/jimmunol.1001360 }} TIM-4 is also able to inhibit naive T cells by non-TIM-1 receptor binding{{cite journal | vauthors = Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT | title = The costimulatory role of TIM molecules | journal = Immunological Reviews | volume = 229 | issue = 1 | pages = 259–70 | date = May 2009 | pmid = 19426227 | pmc = 3217781 | doi = 10.1111/j.1600-065x.2009.00772.x }} but once T cells are active TIM-4 works as positive regulator helping to maintain their activity.{{cite journal | vauthors = Mizui M, Shikina T, Arase H, Suzuki K, Yasui T, Rennert PD, Kumanogoh A, Kikutani H | title = Bimodal regulation of T cell-mediated immune responses by TIM-4 | journal = International Immunology | volume = 20 | issue = 5 | pages = 695–708 | date = May 2008 | pmid = 18367551 | doi = 10.1093/intimm/dxn029 | doi-access = free }}{{Cite journal |last1=Rodriguez-Manzanet |first1=R. |last2=Meyers |first2=J. H. |last3=Balasubramanian |first3=S. |last4=Slavik |first4=J. |last5=Kassam |first5=N. |last6=Dardalhon |first6=V. |last7=Greenfield |first7=E. A. |last8=Anderson |first8=A. C. |author-link8=Ana Anderson |last9=Sobel |first9=R. A. |date=2008-04-01 |title=TIM-4 Expressed on APCs Induces T Cell Expansion and Survival |journal=The Journal of Immunology |language=en |volume=180 |issue=7 |pages=4706–4713 |doi=10.4049/jimmunol.180.7.4706 |issn=0022-1767 |pmc=2948965 |pmid=18354194 |doi-access=free}} TIM-4 expression on macrophages plays an important role in their homeostatic maintenance.{{cite journal | vauthors = Wong K, Valdez PA, Tan C, Yeh S, Hongo JA, Ouyang W | title = Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8712–7 | date = May 2010 | pmid = 20421466 | pmc = 2889355 | doi = 10.1073/pnas.0910929107 | bibcode = 2010PNAS..107.8712W | doi-access = free }}

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.{{cite journal | vauthors = Yang PC, Xing Z, Berin CM, Soderholm JD, Feng BS, Wu L, Yeh C | title = TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy | journal = Gastroenterology | volume = 133 | issue = 5 | pages = 1522–33 | date = November 2007 | pmid = 17915221 | doi = 10.1053/j.gastro.2007.08.006 | doi-access = free }}{{cite journal | vauthors = Feng BS, Chen X, He SH, Zheng PY, Foster J, Xing Z, Bienenstock J, Yang PC | title = 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 | journal = The Journal of Allergy and Clinical Immunology | volume = 122 | issue = 1 | pages = 55–61, 61.e1–7 | date = July 2008 | pmid = 18547633 | doi = 10.1016/j.jaci.2008.04.036 }} 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.{{cite journal | vauthors = Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y, Nagai S, Akiba H, Foretz M, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Takeya M, Viollet B, Yagita H, Jinushi M | title = TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance | journal = Immunity | volume = 39 | issue = 6 | pages = 1070–81 | date = December 2013 | pmid = 24315994 | doi = 10.1016/j.immuni.2013.09.014 | doi-access = free }} Therefore there are studies using the blockade of TIM-4 as a complementary therapy for cancer treatment.{{cite journal | vauthors = Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M | title = Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas | journal = Cancer Immunology, Immunotherapy | volume = 62 | issue = 4 | pages = 629–37 | date = April 2013 | pmid = 23143694 | doi = 10.1007/s00262-012-1371-9 | s2cid = 19381873 | pmc = 11029366 }}

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