Alternative titles; symbols
HGNC Approved Gene Symbol: HAVCR1
Cytogenetic location: 5q33.3 Genomic coordinates (GRCh38) : 5:157,029,413-157,069,407 (from NCBI)
Hepatitis A virus (HAV), a major cause of orally transmitted acute hepatitis, infects primate cells, but not dog or mouse cells, after binding to the HAV cellular receptor (HAVCR). Using RT-PCR with primers specific to the African green monkey Havcr to screen liver and kidney cDNA, Feigelstock et al. (1998) isolated a cDNA encoding human HAVCR1. Sequence analysis predicted that the 359-amino acid type I HAVCR1 glycoprotein, which is 79% identical to the monkey protein, contains a signal sequence; a 109-amino acid cys-rich N-terminal region with only 1 conserved N-glycosylation site; a 163-amino acid TSP-rich region with 3 N-glycosylation sites, 2 of which are conserved; and a 48-amino acid intracellular domain, 12 residues shorter than that of the monkey protein. Northern blot analysis revealed ubiquitous expression of a 4.4-kb HAVCR1 transcript, with highest levels in kidney and testis. An additional 5.5-kb transcript was detected in colon and liver, while spleen, thymus, and peripheral blood leukocytes expressed an additional 7.5-kb transcript. Western blot analysis showed expression of a 53-kD protein.
Crystal Structure
Santiago et al. (2007) determined the crystal structures of the N-terminal ligand-binding domains of murine Tim1 and Tim2 to resolutions of 2.5 and 1.5 angstroms, respectively. The structures revealed an Ig fold, with 4 cys residues bridging a distinctive C-C-prime loop to the GFC beta sheet. Biochemical, mutational, and cell adhesion analyses confirmed that Tim1 is capable of homophilic Tim-Tim interactions, whereas Tim2 forms a dimer that prevents homophilic binding. The features identified in murine Tim1 are conserved in human TIM1.
Infection of canine osteogenic sarcoma cells expressing HAVCR1 with HAV led Feigelstock et al. (1998) to conclude that the protein is indeed a receptor for the virus. Immunofluorescence microscopy demonstrated internalization of HAV by dog cells expressing HAVCR1.
Using real-time RT-PCR, Khademi et al. (2004) found that human Th1 cell lines expressed higher levels of TIM3 (HAVCR2; 606652), whereas Th2 lines expressed higher levels of TIM1. Mononuclear cells from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS; 126200) expressed higher TIM1 mRNA levels than controls. Moreover, higher TIM1 expression was associated with low IFNG (147570) expression in CSF mononuclear cells and with clinical remissions. In contrast, TIM3 expression correlated well with high expression of IFNG and TNF (191160). Khademi et al. (2004) concluded that differential expression of TIMs by Th1 and Th2 cells may be implicated in different phases of an autoimmune disease.
Using a monoclonal antibody to mouse Tim1, Umetsu et al. (2005) showed that Tim1 was expressed after activation of naive T cells and on T cells differentiated in Th2-polarizing conditions. Stimulation of the T-cell receptor of CD4 (186940)-positive T cells together with anti-Tim1 greatly enhanced T-cell proliferation and Th2 cytokine production. In vivo administration of anti-Tim1 prevented development of respiratory tolerance on exposure to allergens, resulting in pulmonary inflammation and allergen-induced airway hyperreactivity. Umetsu et al. (2005) proposed that immunotherapies regulating TIM1 function may downmodulate allergic inflammatory diseases.
Using FACS analysis, Meyers et al. (2005) showed that mouse T cells expressed a Tim4 (TIM4D; 610096) ligand, which they identified as Tim1, and Tim4 bound T cells expressing Tim1. Administration of either Tim1-Ig or Tim4-Ig fusion proteins resulted in hyperproliferation of T lymphocytes in vivo. Meyers et al. (2005) concluded that the TIM1-TIM4 interaction regulates T-cell proliferation.
Using flow cytometric analysis, de Souza et al. (2005) demonstrated that lung-draining lymph nodes from immunized, but not naive, mice expressed Tim1. Ectopic expression of Tim1 during mouse T-cell differentiation led to production of the Th2-type cytokine Il4 (147780), but not the Th1-type cytokine Ifng. Reporter analysis showed that activation of TIM1-expressing mouse and human T cells stimulated NFAT (see 600489)/AP1 (165160) transcription factors, and this costimulation was dependent on tyr276 in the cytoplasmic tail of TIM1. De Souza et al. (2005) concluded that TIM1 provides a costimulatory signal that influences effector T-cell differentiation and TCR-dependent activation of the IL4 promoter and NFAT/AP1 transcription factors.
Miyanishi et al. (2007) established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4. Miyanishi et al. (2007) found that Tim4 and Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1 or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. Miyanishi et al. (2007) concluded that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signaling in which exosomes are involved.
Using immunofluorescence microscopy, Ichimura et al. (2008) localized Kim1 directly adjacent to apoptotic cells and necrotic debris in the lumens of rat kidney tubules following ischemic injury. Kim1-expressing epithelial cells internalized apoptotic bodies, and Kim1 was directly responsible for phagocytosis in cultured primary rat tubule epithelial cells and in porcine and canine epithelial cell lines. The ectodomain of Kim1 specifically recognized cell-surface phosphatidylserine and oxidized lipoproteins expressed by apoptotic tubular epithelial cells.
By screening mouse hematopoietic cell lines with a fusion protein containing the extracellular domain of mouse Lmir5 (CD300LB; 610705), Yamanishi et al. (2010) identified Tim1 and Tim4 as possible ligands. Binding occurred between the Ig-like domains of Lmir5 and Tim1, and binding did not affect Tim1- or Tim4-mediated phagocytosis of apoptotic cells. Stimulation with Tim1 or Tim4 induced Lmir5-mediated activation of mast cells. Mice lacking Lmir5 had suppressed neutrophil recruitment to the dorsal air pouch, and Lmir5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which Tim1 expression was upregulated. Yamanishi et al. (2010) concluded that TIM1 is an endogenous ligand for LMIR5 and that the TIM1-LMIR5 interaction has a physiologic role in immune regulation by myeloid cells.
Bod et al. (2023) demonstrated that TIM1 expression marked a subset of activated B cells expressing multiple T-cell checkpoint molecules in both mouse and human tumors. B cell-specific deletion of Tim1 inhibited tumor growth in mouse tumor models. Antibody blockade of Tim1 resulted in tumor growth control in both transplanted and spontaneous tumor models, which required Tim1 expression on B cells, but not on other cell types. Tim1 surface expression was regulated by type I interferon (see 147660), and Tim1 expression restrained B-cell antigen presentation. As a result, loss of Tim1 enhanced the type I interferon response in B cells, which augmented B-cell activation, increased antigen presentation and costimulation, and resulted in increased expansion of tumor-specific effector T cells.
By homology of synteny with the mouse Tim1 gene and database analysis, McIntire et al. (2001) mapped the HAVCR1 gene to 5q33.2.
McIntire et al. (2003) investigated whether the interaction between hepatitis A virus and TIM1 on lymphocytes can modify T cells in a way that protects against atopy (see 147050), and whether polymorphisms in TIM1 can alter susceptibility to atopy. They identified a 6-amino acid insertion at residue 157, designated 157insMTTTVP (606518.0001), a deletion of a threonine residue at codon 195, which they designated 195delT, and an ala206-to-thr (A206T) substitution. In a cross-sectional study of 375 individuals who were evaluated by history and tested serologically for atopy and prior HAV infection, they found that HAV seropositivity protected against atopy, but only in the individuals with the 157insMTTTVP variant of TIM1 (p = 0.0005). This allele was carried by 63% of Caucasians, 46% of Asians, and 64% of African Americans in their study population.
By screening for polymorphisms of TIM1, TIM3, and TIM4 in 478 Thai patients infected with Plasmodium falciparum (see 611162), Nuchnoi et al. (2008) identified a statistically significant association between protection against cerebral malaria and a TIM1 promoter haplotype consisting of 3 derived alleles, -1637G-A (rs7702919), -1549G-C (rs41297577), and -1454G-A (rs41297579). Allele-specific transcription quantification analysis revealed that TIM1 mRNA levels were higher for the protective promoter haplotype than for the other promoter haplotype. Nuchnoi et al. (2008) proposed that engagement of TIM1 and T-cell receptor stimulation may induce antiinflammatory Th2 cytokine production and protect from development of cerebral malaria by downregulating inflammatory cytokines such as TNF and IFNG.
A decline in the frequency of HAV and other fecal-oral pathogens in industrialized countries in the last half of the 20th century was accompanied by an increase in the frequency of asthma (600807), which is linked to chromosome 5q and other loci (Wills-Karp et al., 2001). TH2-type cytokines are encoded by genes found on 5q23-q35, which is homologous to a region on mouse chromosome 11. McIntire et al. (2001) generated congenic mice, designated HBA mice, containing a segment of chromosome 11 inherited from DBA/2 mice, which have low TH2 responses on the high-responder BALB/c background. HBA mice produced significantly less IL4, IL13 (147683), and IL10 (124092) and had lower antigen-induced airway hyperreactivity (AHR) than did BALB/c mice. McIntire et al. (2001) proposed the existence of a T-cell and airway phenotype regulator (Tapr) locus on mouse chromosome 11. By simple sequence length polymorphism and backcross analyses, they narrowed the localization of Tapr to a region more than 5 cM centromeric to the IL4 cytokine cluster. The Tapr locus was nonrecombinant with a marker within the homolog of the rat kidney injury molecule-1 gene (Kim1). By homology of synteny and database analysis, the authors linked the Tapr locus to human chromosome 5q33.2. By EST database analysis, McIntire et al. (2001) identified HAVCR1 as a human homolog of rat Kim1. By PCR of activated mouse splenocytes with primers based on the rat Kim1 sequence, McIntire et al. (2001) obtained cDNAs encoding mouse Tim1 (T-cell, immunoglobulin domain, mucin domain protein-1) and Tim2. The deduced 305-amino acid Tim1 and Tim2 proteins are 42% and 32% identical to HAVCR1, respectively. A third Tim protein, Tim3, encodes a 281-amino acid protein. Comparison of BALB/c and HBA Tim sequences revealed polymorphisms in Tim1 and Tim3, but none were identified in Tim2. The Tim1 polymorphisms correlated with the development of higher TH2 responses in BALB/c mice compared with HBA mice. McIntire et al. (2001) suggested that the interaction of HAV with HAVCR1, the human ortholog of Tim1, may reduce TH2 differentiation and reduce the likelihood of developing asthma.
This variant, formerly titled ATOPY, RESISTANCE TO, has been reclassified as a polymorphism.
By sequencing cDNA from human lymphocytes, McIntire et al. (2003) identified a 6-amino acid insertion at residue 157 of the TIM1 gene product, which they designated 157insMTTTVP (single-letter amino acid code), as a polymorphism. The insertion is located at the center of an extracellular mucin-like region that is required for efficient uncoating of the hepatitis A virus (HAV) and, because the insertion lengthens this critical region by 12 to 14%, McIntire et al. (2003) suggested that it may affect the efficiency of viral entry. To determine the effect of the insertion on the occurrence of atopy (see 147050), they performed a cross-sectional study of 375 individuals who were evaluated by history and tested serologically for atopy and prior hepatitis A infection. They found that HAV seropositivity protected against atopy, but only in individuals with the 157insMTTTVP variant (p = 0.0005). McIntire et al. (2003) suggested that the protective effects of HAV depend upon a common TIM1 allele, which they found to be carried by 63% of Caucasians, 46% of Asians, and 64% of African Americans in their study population. They noted that prior to 1970, the seroprevalence of antibodies against HAV approached 100% in western countries, and infection with HAV may have protected many individuals against atopy. Since then, the reduction in average family size and improvements in public health led to an anti-HAV seroprevalence of only 25 to 30%, whereas the prevalence of atopic diseases doubled. McIntire et al. (2003) concluded that their findings indicated that interaction between HAV and TIM1 genotype may contribute to the etiology of atopic diseases and provided a mechanism to account for the hygiene hypothesis.
By examining 30 Argentine patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study, Kim et al. (2011) found an association with the 6-amino acid insertion in TIM1. Binding assays showed that TIM1 containing the insertion bound HAV more efficiently than TIM1 without the insertion. Expression of TIM1 containing the insertion in human natural killer T cells resulted in greater cytotoxic activity against HAV-infected liver cells compared with the shorter TIM1 protein. Kim et al. (2011) proposed that HAV infection has driven selection of shorter forms of TIM1 that bind HAV less efficiently and thereby protect against HAV-induced disease, but with the consequence of a predisposition to inflammation associated with asthma and allergy.
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Yamanishi, Y., Kitaura, J., Izawa, K., Kaitani, A., Komeno, Y., Nakamura, M., Yamazaki, S., Enomoto, Y., Oki, T., Akiba, H., Abe, T., Komori, T., Morikawa, Y., Kiyonari, H., Takai, T., Okumura, K., Kitamura, T. TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. J. Exp. Med. 207: 1501-1511, 2010. [PubMed: 20566714] [Full Text: https://doi.org/10.1084/jem.20090581]