Immunoglobulin A (IgA) Is a Natural Ligand of Hepatitis A Virus Cellular Receptor 1 (HAVCR1), and the Association of IgA with HAVCR1 Enhances Virus-Receptor Interactions

Abstract

The hepatitis A virus (HAV) cellular receptor 1 (HAVCR1/ TIM1) is a type 1 integral membrane glycoprotein consisting of a characteristic six-cysteine immunoglobulin (Ig)-like domain extended above the cell surface by a mucin-like domain that contains a variable number of threonine, serine, and proline (TSP) hexameric repeats (19). The monkey (19) and human (13) HAVCR1/TIM1 were the first identified members of the T-cell immunoglobulin mucin (TIM) family, an immunologically important group of receptors (22,28,29,32) that is conserved in vertebrates. Although HAV is a hepatotropic virus that causes acute hepatitis in humans, infection with HAV has been shown to greatly reduce the risk of developing asthma and allergy in humans (26,27). Because the gene encoding HAVCR1/TIM1 has been shown to be an important asthma and allergy susceptibility gene in humans (14,15,29,30), it appears that HAVCR1/TIM1 plays a critical role in regulating T-cell differentiation (29) and the development of atopy (30). However, the precise immunological mechanisms by which HAV infection prevents atopy and the exact mechanisms by which HAVCR1/TIM1 functions normally in the absence of HAV infection to regulate immune responses are not fully understood.In mice, Tim-1 has been shown to be an important T-cell costimulatory molecule, which is preferentially expressed on T helper 2 (Th2) cells (48). Cross-linking of mouse Tim-1 enhances T-cell proliferation and cytokine production and prevents the induction of respiratory tolerance, resulting in airway hyperreactivity, a cardinal feature of asthma (48). Tim-1 costimulation requires its cytoplasmic tail and a conserved tyrosine that can be phosphorylated (8). In humans, HAVCR1/TIM1 is expressed in Th2 cell lines, is associated with remission in patients with multiple sclerosis (21), and is highly expressed in kidneys (19) primarily after injury (16) or in tumors (50). Recently, mouse Tim-4, a TIM family member expressed on antigen-presenting cells (APCs), has been shown to be a ligand for Tim-1 (31). However, whether human TIM4, the ortholog of mouse Tim-4, functions as a ligand of human HAVCR1/ TIM1 is not known.Using an expression cloning strategy with a soluble form of the HAVCR1/TIM1 containing the HAVCR1/TIM1 Ig variable-like (IgV) region fused to the Fc fragment of a human IgG1 antibody [HAVCR1/TIM1(IgV)-Fc], we identified IgA as a specific ligand of HAVCR1/TIM1. The interaction between HAVCR1/TIM1 and IgA is specific, since it was blocked with monoclonal antibody (MAb) to immunoglobulin alpha 1 heavy (Ig␣1) or lambda light (Ig) chain, with anti-

Internal ribosomal entry‐site activities of clinical isolate‐derived hepatitis A virus and inhibitory effects of amantadine

“…It was reported that an antibiotic resistance titration assay (ARTA) is useful for HAV neutralization including virus‐receptor interaction 33,34 . We also tested the effects of amantadine against HAV IRES of clinical isolates and confirmed the effects against fulminant hepatitis clones.…”

Apoptotic Cells Activate NKT Cells through T Cell Ig-Like Mucin-Like–1 Resulting in Airway Hyperreactivity

“…Previous reports have shown that TIM-1 is expressed on several different cell types, including activated CD4 T cells (4, 5) and mast cells (62), and that several different ligands have been proposed for TIM-1, including TIM-1 itself, TIM-4, and IgAl (30, 54, 63, 64). In man, TIM-1 is also the receptor for the hepatitis A virus (65), and infection with hepatitis A virus has been shown to reduce greatly the likelihood of developing asthma and allergy (66, 67).…”

Vectorial Entry and Release of Hepatitis A Virus in Polarized Human Hepatocytes

“…Apical to basolateral transcytosis of HAV, mediated by the polymeric immunoglobulin receptor, has been shown to occur in polarized epithelial MDCK cells, and a similar IgA-mediated mechanism may be used by HAV in gut epithelia to achieve access to the circulation (19). IgA is a natural ligand of HAVCR1, and the association of IgA with HAVCR1 enhances virus-receptor interactions (63). It is of note, however, that virions would have to avoid uncoating in susceptible enteric cells in order to reach the bloodstream intact for transmission to the liver, and virus-specific IgA would need to have survived along with the virus in the environment (and the gut) to effect this function.…”