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Gene Review

Havcr1  -  hepatitis A virus cellular receptor 1

Mus musculus

Synonyms: AI503787, HAVcr-1, Hepatitis A virus cellular receptor 1 homolog, KIM-1, Kidney injury molecule 1, ...
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Disease relevance of Havcr1

  • TIM-1 is genetically linked to asthma and is a receptor for hepatitis A virus, but the endogenous ligand of TIM-1 is not known [1].
  • In vivo, the use of antibody to TIM-1 plus antigen substantially increased production of both interleukin 4 and interferon-gamma in unpolarized T cells, prevented the development of respiratory tolerance, and increased pulmonary inflammation [2].
  • T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis [3].
  • These results are the first to suggest that TIM-1 antibody may serve as a potent adjuvant in the development of new influenza virus vaccines [4].
  • We investigated the ability of Abs blocking Tim-1 or Tim-3 ligand-binding activity to prevent and treat murine experimental allergic conjunctivitis (EC), a Th2-mediated disease [5].

Psychiatry related information on Havcr1


High impact information on Havcr1

  • Three of the family members (Tim-1, Tim-3, and Tim-4) are conserved between mouse and man [7].
  • Genomic association of the TIM family and polymorphisms in both Tim-1 and Tim-3 in different immune-mediated diseases suggest that the family may have an important role in regulating immunity, both in terms of normal immune responses and in diseases like autoimmunity and asthma [7].
  • This increased avidity for peptide-MHC depends on TCR reorganization and is sensitive to the cholesterol content of the T cell membrane [8].
  • TIM-1 induces T cell activation and inhibits the development of peripheral tolerance [2].
  • Here we show that TIM-4, which is expressed by antigen-presenting cells, is the ligand for TIM-1 [1].

Biological context of Havcr1


Anatomical context of Havcr1

  • Light microscopy and electron microscopy revealed a close association between the T cell membrane and the cell wall of N. asteroides, with possible damage to the latter structure [14].
  • Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-gamma mRNA in cerebrospinal fluid mononuclear cells [3].
  • Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems [15].
  • These studies suggest that TIM-1 can regulate macrophage activation and alter the co-stimulatory properties of macrophages and thus may contribute to allergic inflammatory diseases such as asthma [16].
  • We postulate that an antigen-Ia complex may provide for close physical interactions between effector and target cells and may approximate putative T cell membrane-bound activating molecules (as yet unidentified) with the macrophage plasma membrane [17].

Associations of Havcr1 with chemical compounds

  • Finally, we provide evidence that TIM-1 can be phosphorylated on tyrosine and that TIM-1 costimulation requires its cytoplasmic tail and the conserved tyrosine within that domain [18].
  • These results constitute evidence that TIM-1 directly couples to phosphotyrosine-dependent intracellular signaling pathways [18].
  • Transfer of the ADP-ribose moiety from NAD onto extracellular arginine residues on T-cell membrane proteins is mediated by glycosylphosphatidylinositol-linked cell surface ARTs [19].
  • These results suggest that cyclosporin A mediates its effect on cells through more than one cyclophilin and that cyclosporin A-induced misfolding of T-cell membrane proteins normally mediated by CPH2 plays a role in immunosuppression [20].
  • Because L-lactate may be transported bidirectionally through the T cell membrane in vivo, different physiologic roles of L-lactate transport are discussed [21].

Regulatory relationships of Havcr1


Other interactions of Havcr1

  • Ectopic expression of TIM-1 during T cell differentiation results in a significant increase in the number of cells producing IL-4 but not IFN-gamma [18].
  • Furthermore, TIM-1 expression provides a costimulatory signal that increases transcription from the IL-4 promoter and from isolated nuclear factor of activated T cells/activating protein-1 (NFAT/AP-1) elements [18].
  • Mouse T cell membrane proteins Rt6-1 and Rt6-2 are arginine/protein mono(ADPribosyl)transferases and share secondary structure motifs with ADP-ribosylating bacterial toxins [23].
  • The data suggest that other T cell membrane molecules contribute to activation of Mphi effector function by stimulation of M phi TNF-alpha production [24].
  • CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown [25].

Analytical, diagnostic and therapeutic context of Havcr1

  • In vitro stimulation of CD4(+) T cells with a TIM-1-specific monoclonal antibody and T cell receptor ligation enhanced T cell proliferation; in T(H)2 cells, such costimulation greatly enhanced synthesis of interleukin 4 but not interferon-gamma [2].
  • Our studies suggest that immunotherapies that regulate TIM-1 function may downmodulate allergic inflammatory diseases [2].
  • Immunofluorescence analysis indicated that mouse Ltk- cells transfected with HAVcr-1 cDNA gained limited susceptibility to HAV infection, which was blocked by treatment with monoclonal antibody 190/4 [10].
  • A sensitive radioimmunoassay was constructed for detection of the T cell membrane components [26].
  • No alloantibodies directed to the T cell membrane components, the putative human homologues of mouse TL antigens, were found in any of the human tissue typing sera tested [26].


  1. TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T cell proliferation. Meyers, J.H., Chakravarti, S., Schlesinger, D., Illes, Z., Waldner, H., Umetsu, S.E., Kenny, J., Zheng, X.X., Umetsu, D.T., DeKruyff, R.H., Strom, T.B., Kuchroo, V.K. Nat. Immunol. (2005) [Pubmed]
  2. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Umetsu, S.E., Lee, W.L., McIntire, J.J., Downey, L., Sanjanwala, B., Akbari, O., Berry, G.J., Nagumo, H., Freeman, G.J., Umetsu, D.T., DeKruyff, R.H. Nat. Immunol. (2005) [Pubmed]
  3. T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. Khademi, M., Illés, Z., Gielen, A.W., Marta, M., Takazawa, N., Baecher-Allan, C., Brundin, L., Hannerz, J., Martin, C., Harris, R.A., Hafler, D.A., Kuchroo, V.K., Olsson, T., Piehl, F., Wallström, E. J. Immunol. (2004) [Pubmed]
  4. Vaccination with cell immunoglobulin mucin-1 antibodies and inactivated influenza enhances vaccine-specific lymphocyte proliferation, interferon-gamma production and cross-strain reactivity. Soo Hoo, W., Jensen, E.R., Saadat, A., Nieto, D., Moss, R.B., Carlo, D.J., Moll, T. Clin. Exp. Immunol. (2006) [Pubmed]
  5. Antibodies to T-cell Ig and mucin domain-containing proteins (Tim)-1 and -3 suppress the induction and progression of murine allergic conjunctivitis. Fukushima, A., Sumi, T., Fukuda, K., Kumagai, N., Nishida, T., Akiba, H., Okumura, K., Yagita, H., Ueno, H. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  6. Uncovered: the family relationship of a T-cell-membrane protein and bacterial toxins. Koch-Nolte, F., Haag, F., Kastelein, R., Bazan, F. Immunol. Today (1996) [Pubmed]
  7. TIM Family of Genes in Immunity and Tolerance. Kuchroo, V.K., Meyers, J.H., Umetsu, D.T., Dekruyff, R.H. Adv. Immunol. (2006) [Pubmed]
  8. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Fahmy, T.M., Bieler, J.G., Edidin, M., Schneck, J.P. Immunity (2001) [Pubmed]
  9. Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo. Ferran, C., Dautry, F., Mérite, S., Sheehan, K., Schreiber, R., Grau, G., Bach, J.F., Chatenoud, L. J. Clin. Invest. (1994) [Pubmed]
  10. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus. Kaplan, G., Totsuka, A., Thompson, P., Akatsuka, T., Moritsugu, Y., Feinstone, S.M. EMBO J. (1996) [Pubmed]
  11. Regulation of tyrosine phosphorylation in isolated T cell membrane by inhibition of protein tyrosine phosphatases. Jin, Y.J., Friedman, J., Burakoff, S.J. J. Immunol. (1998) [Pubmed]
  12. Affinity enhancement and transmembrane signaling are associated with distinct epitopes on the CD8 alpha beta heterodimer. Eichmann, K., Ehrfeld, A., Falk, I., Goebel, H., Kupsch, J., Reimann, A., Zgaga-Griesz, A., Saizawa, K.M., Yachelini, P., Tomonari, K. J. Immunol. (1991) [Pubmed]
  13. Susceptibility to lipid peroxidation and accumulation of fluorescent products with age is greater in T-cells than B-cells. Hendricks, L.C., Heidrick, M.L. Free Radic. Biol. Med. (1988) [Pubmed]
  14. Immunologically specific direct T lymphocyte-mediated killing of Nocardia asteroides. Deem, R.L., Doughty, F.A., Beaman, B.L. J. Immunol. (1983) [Pubmed]
  15. Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems. Gielen, A.W., Lobell, A., Lidman, O., Khademi, M., Olsson, T., Piehl, F. J. Neuroimmunol. (2005) [Pubmed]
  16. TIM-1 regulates macrophage cytokine production and B7 family member expression. Hein, R.M., Woods, M.L. Immunol. Lett. (2007) [Pubmed]
  17. Cell contact-mediated macrophage activation for antileishmanial defence: mapping of the genetic restriction to the I region of the MHC. Sypek, J.P., Wyler, D.J. Clin. Exp. Immunol. (1985) [Pubmed]
  18. T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation. de Souza, A.J., Oriss, T.B., O'malley, K.J., Ray, A., Kane, L.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Generation and characterization of ecto-ADP-ribosyltransferase ART2.1/ART2.2-deficient mice. Ohlrogge, W., Haag, F., Löhler, J., Seman, M., Littman, D.R., Killeen, N., Koch-Nolte, F. Mol. Cell. Biol. (2002) [Pubmed]
  20. An endoplasmic reticulum-specific cyclophilin. Hasel, K.W., Glass, J.R., Godbout, M., Sutcliffe, J.G. Mol. Cell. Biol. (1991) [Pubmed]
  21. Demonstration of organic anion transport in T lymphocytes. L-lactate and fluo-3 are target molecules. Sommer, F., Bischof, S., Röllinghoff, M., Lohoff, M. J. Immunol. (1994) [Pubmed]
  22. Induction of concanavalin A dose-dependent T-cell growth factor production by insertion of T-cell membrane components into the AKR thymic lymphoma BW 5147. Lindqvist, C., Shapiro, I.M., Wigzell, H. Scand. J. Immunol. (1986) [Pubmed]
  23. Mouse T cell membrane proteins Rt6-1 and Rt6-2 are arginine/protein mono(ADPribosyl)transferases and share secondary structure motifs with ADP-ribosylating bacterial toxins. Koch-Nolte, F., Petersen, D., Balasubramanian, S., Haag, F., Kahlke, D., Willer, T., Kastelein, R., Bazan, F., Thiele, H.G. J. Biol. Chem. (1996) [Pubmed]
  24. T cells which do not express membrane tumor necrosis factor-alpha activate macrophage effector function by cell contact-dependent signaling of macrophage tumor necrosis factor-alpha production. Suttles, J., Miller, R.W., Tao, X., Stout, R.D. Eur. J. Immunol. (1994) [Pubmed]
  25. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. Linsley, P.S., Greene, J.L., Tan, P., Bradshaw, J., Ledbetter, J.A., Anasetti, C., Damle, N.K. J. Exp. Med. (1992) [Pubmed]
  26. Human cell membrane components dominant in T cell lineage: identification and characterization of human TL-like antigens. Tanigaki, N., Tokuyama, H., Fukunishi, T., Minowada, J., Pressman, D. J. Immunol. (1979) [Pubmed]
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