| Structural highlights
Function
HAVR2_MOUSE Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand (PubMed:18006747). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556006, PubMed:18006747). In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits (By similarity). In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN (PubMed:21807895). Expressed on Treg cells can inhibit Th17 cell responses (By similarity). Receptor for LGALS9. Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6 (PubMed:22863785). Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth (PubMed:20937702). However, the function as receptor for LGALS9 has been challenged (By similarity). Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes (PubMed:24567532). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent (PubMed:20083673). May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells (PubMed:19224762). Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells (PubMed:20083673). Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha (PubMed:18006747). In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes (PubMed:22842346). Can enhance mast cell production of Th2 cytokines Il-4, IL-6 and IL-13 (PubMed:17620455). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity (By similarity). Negatively regulates NK cell function in LPS-induced endotoxic shock (PubMed:25337993).[UniProtKB:Q8TDQ0][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
T cell/transmembrane, Ig, and mucin (TIM) proteins, identified using a congenic mouse model of asthma, critically regulate innate and adaptive immunity. TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), exposed on the surfaces of apoptotic cells. Herein, we show with structural and biological studies that TIM-3 is also a receptor for PtdSer that binds in a pocket on the N-terminal IgV domain in coordination with a calcium ion. The TIM-3/PtdSer structure is similar to that of TIM-4/PtdSer, reflecting a conserved PtdSer binding mode by TIM family members. Fibroblastic cells expressing mouse or human TIM-3 bound and phagocytosed apoptotic cells, with the BALB/c allelic variant of mouse TIM-3 showing a higher capacity than the congenic C.D2 Es-Hba-allelic variant. These functional differences were due to structural differences in the BC loop of the IgV domain of the TIM-3 polymorphic variants. In contrast to fibroblastic cells, T or B cells expressing TIM-3 formed conjugates with but failed to engulf apoptotic cells. Together these findings indicate that TIM-3-expressing cells can respond to apoptotic cells, but the consequence of TIM-3 engagement of PtdSer depends on the polymorphic variants of and type of cell expressing TIM-3. These findings establish a new paradigm for TIM proteins as PtdSer receptors and unify the function of the TIM gene family, which has been associated with asthma and autoimmunity and shown to modulate peripheral tolerance.
T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells.,DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM J Immunol. 2010 Feb 15;184(4):1918-30. Epub 2010 Jan 18. PMID:20083673[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002 Jan 31;415(6871):536-41. PMID:11823861 doi:10.1038/415536a
- ↑ Sabatos CA, Chakravarti S, Cha E, Schubart A, Sánchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003 Nov;4(11):1102-10. PMID:14556006 doi:10.1038/ni988
- ↑ Nakae S, Iikura M, Suto H, Akiba H, Umetsu DT, Dekruyff RH, Saito H, Galli SJ. TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells. Blood. 2007 Oct 1;110(7):2565-8. PMID:17620455 doi:10.1182/blood-2006-11-058800
- ↑ Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007 Nov 16;318(5853):1141-3. PMID:18006747 doi:10.1126/science.1148536
- ↑ Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009 Apr 16;113(16):3821-30. PMID:19224762 doi:10.1182/blood-2008-10-185884
- ↑ DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010 Feb 15;184(4):1918-30. Epub 2010 Jan 18. PMID:20083673 doi:http://dx.doi.org/10.4049/jimmunol.0903059
- ↑ Jayaraman P, Sada-Ovalle I, Beladi S, Anderson AC, Dardalhon V, Hotta C, Kuchroo VK, Behar SM. Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med. 2010 Oct 25;207(11):2343-54. PMID:20937702 doi:10.1084/jem.20100687
- ↑ Lee J, Su EW, Zhu C, Hainline S, Phuah J, Moroco JA, Smithgall TE, Kuchroo VK, Kane LP. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol. 2011 Oct;31(19):3963-74. PMID:21807895 doi:10.1128/MCB.05297-11
- ↑ Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012 Sep;13(9):832-42. PMID:22842346 doi:10.1038/ni.2376
- ↑ Gorman JV, Starbeck-Miller G, Pham NL, Traver GL, Rothman PB, Harty JT, Colgan JD. Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol. 2014 Apr 1;192(7):3133-42. PMID:24567532 doi:10.4049/jimmunol.1302290
- ↑ Hou H, Liu W, Wu S, Lu Y, Peng J, Zhu Y, Lu Y, Wang F, Sun Z. Tim-3 negatively mediates natural killer cell function in LPS-induced endotoxic shock. PLoS One. 2014 Oct 22;9(10):e110585. PMID:25337993 doi:10.1371/journal.pone.0110585
- ↑ Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, Angin M, Wakeham A, Greenfield EA, Sobel RA, Okada H, McKinnon PJ, Mak TW, Addo MM, Anderson AC, Kuchroo VK. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion. Nat Med. 2012 Sep;18(9):1394-400. PMID:22863785 doi:10.1038/nm.2871
- ↑ DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010 Feb 15;184(4):1918-30. Epub 2010 Jan 18. PMID:20083673 doi:http://dx.doi.org/10.4049/jimmunol.0903059
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