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Gene Review

HAVCR2  -  hepatitis A virus cellular receptor 2

Homo sapiens

Synonyms: FLJ14428, HAVcr-2, Hepatitis A virus cellular receptor 2, KIM-3, T-cell immunoglobulin and mucin domain-containing protein 3, ...
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Disease relevance of HAVCR2


High impact information on HAVCR2

  • 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].
  • Dysregulated T cell expression of TIM3 in multiple sclerosis [8].
  • TIM-3 is similarly expressed on human Th1 cells and not on Th2 cells, which suggests that TIM-3 might also contribute to Th1 regulation in humans [2].
  • Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes [3].
  • None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes [9].

Chemical compound and disease context of HAVCR2

  • We evaluated the pharmacokinetic properties of Kryobulin TIM3, a new heat-treated Factor VIII concentrate which has recently become available in Europe. Twelve patients with classic hemophilia were studied [10].

Biological context of HAVCR2


Anatomical context of HAVCR2

  • A member of TIM family, TIM-3 is selectively expressed on the surface of differentiated Th1 cells [1].
  • Unlike Tim-1, which is expressed in renal epithelia and cancer, Tim-3 has not been described in cells other than neuronal or T-cells [12].
  • We have cloned Tim-3 from an immortalized liver cell carcinoma line and identified a highly conserved tyrosine in the intracellular tail of Tim-3 (Y265) [12].
  • In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4(+)CD25(+) regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses [13].
  • Human Tim-3 mRNA was highly expressed in monocytes or monocyte-derived cells, and the expression level decreased when DC underwent maturation and activation [14].

Associations of HAVCR2 with chemical compounds

  • A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9 [12].
  • Human Tim-3 is a 301-residue type I membrane protein whose extracellular region contains a Cys-rich Ig-like domain and a mucin domain, the characteristics of Tim proteins [14].

Other interactions of HAVCR2

  • These results strongly suggest that -574T>G and 4259G>T polymorphism of the Tim-3 might be associated with susceptibility to RA [1].
  • Our results strongly suggest that the -574T > G polymorphism of Tim-3 might be associated with the susceptibility of atopic diseases such as asthma and allergic rhinitis [11].
  • In tuberculous pleural effusion, ratios of IFN-gamma and IL-12 to IL-4 were significantly higher, and T-cells showed the expression of Tim-3 messenger RNA [15].
  • These positive costimulatory signals are counterbalanced by signals that dampen down immune responses and include CTLA-4, PD-1 and the recently described Ig superfamily members BTLA and TIM-3 [16].

Analytical, diagnostic and therapeutic context of HAVCR2

  • Using RT-PCR we demonstrate that Tim-3 is expressed in malignant and non-malignant epithelial tissues [12].
  • We demonstrated that HeLa cells, which are refractory to HAV infection, acquired a limited susceptibility to HAV infection after stably overexpressing human Tim-3 as confirmed by Western blot analysis using anti-Tim-3 antibody, but Tim-3-Fc fusion protein had no direct HAV-binding activity [14].


  1. The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Chae, S.C., Park, Y.R., Shim, S.C., Yoon, K.S., Chung, H.T. Immunol. Lett. (2004) [Pubmed]
  2. TIM-3 in autoimmunity. Anderson, A.C., Anderson, D.E. Curr. Opin. Immunol. (2006) [Pubmed]
  3. Preferential Involvement of Tim-3 in the Regulation of Hepatic CD8+ T Cells in Murine Acute Graft-versus-Host Disease. Oikawa, T., Kamimura, Y., Akiba, H., Yagita, H., Okumura, K., Takahashi, H., Zeniya, M., Tajiri, H., Azuma, M. J. Immunol. (2006) [Pubmed]
  4. Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33. Graves, P.E., Siroux, V., Guerra, S., Klimecki, W.T., Martinez, F.D. J. Allergy Clin. Immunol. (2005) [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. Lack of TIM-3 immunoregulation in multiple sclerosis. Yang, L., Anderson, D.E., Kuchroo, J., Hafler, D.A. J. Immunol. (2008) [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. Dysregulated T cell expression of TIM3 in multiple sclerosis. Koguchi, K., Anderson, D.E., Yang, L., O'Connor, K.C., Kuchroo, V.K., Hafler, D.A. J. Exp. Med. (2006) [Pubmed]
  9. Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population. Gao, P.S., Mathias, R.A., Plunkett, B., Togias, A., Barnes, K.C., Beaty, T.H., Huang, S.K. J. Allergy Clin. Immunol. (2005) [Pubmed]
  10. Pharmacokinetics of a new heat-treated concentrate of factor VIII estimated by model-independent methods. Longo, G., Matucci, M., Messori, A., Morfini, M., Rossi-Ferrini, P. Thromb. Res. (1986) [Pubmed]
  11. The association of TIM-3 gene polymorphism with atopic disease in Korean population. Chae, S.C., Park, Y.R., Lee, Y.C., Lee, J.H., Chung, H.T. Hum. Immunol. (2004) [Pubmed]
  12. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. van de Weyer, P.S., Muehlfeit, M., Klose, C., Bonventre, J.V., Walz, G., Kuehn, E.W. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  13. Regulation of T cell dependent immune responses by TIM family members. Mariat, C., Sánchez-Fueyo, A., Alexopoulos, S.P., Kenny, J., Strom, T.B., Zheng, X.X. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2005) [Pubmed]
  14. Human membrane protein Tim-3 facilitates hepatitis A virus entry into target cells. Sui, L., Zhang, W., Chen, Y., Zheng, Y., Wan, T., Zhang, W., Yang, Y., Fang, G., Mao, J., Cao, X. Int. J. Mol. Med. (2006) [Pubmed]
  15. T-helper type 1/T-helper type 2 balance in malignant pleural effusions compared to tuberculous pleural effusions. Okamoto, M., Hasegawa, Y., Hara, T., Hashimoto, N., Imaizumi, K., Shimokata, K., Kawabe, T. Chest (2005) [Pubmed]
  16. The role of ICOS and other costimulatory molecules in allergy and asthma. Coyle, A.J., Gutierrez-Ramos, J.C. Springer Semin. Immunopathol. (2004) [Pubmed]
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