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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

Laboratory of Hepatitis and Related Emerging Agents, CBER, Food and Drug Administration, Bethesda, Maryland 20892,¹ Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115,² Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611,³ Division of Immunology, Karp Laboratories, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115⁴

Received 24 July 2006/ Accepted 7 January 2007

The hepatitis A virus cellular receptor 1 (HAVCR1/TIM1), a member of the T-cell immunoglobulin mucin (TIM) family, is an important atopy susceptibility gene in humans. The exact natural function of HAVCR1/TIM1 and the inverse association between HAV infection and prevention of atopy are not well understood. To identify natural ligands of human HAVCR1/TIM1, we used an expression cloning strategy based on the binding of dog cells transfected with a human lymph node cDNA library to a HAVCR1/TIM1 Fc fusion protein. The transfected cells that bound to the human HAVCR1/TIM1 Fc contained cDNA of human immunoglobulin alpha 1 heavy (Ig1) and lambda light (Ig) chain and secreted human IgA1 antibody that bound to the cell surface. Cotransfection of the isolated Ig1 and Ig cDNAs to naïve dog cells resulted in the secretion of IgA1 that bound to HAVCR1/TIM1 Fc but not to a poliovirus receptor Fc fusion protein in a capture enzyme-linked immunosorbent assay. The interaction of HAVCR1/TIM1 with IgA was inhibited by monoclonal antibodies (MAbs) against Ig1 and Ig, excess IgA1, or anti-HAVCR1/TIM1 MAb. IgA did not inhibit HAV infection of African green monkey cells, suggesting that the IgA and the virus binding sites are in different epitopes on HAVCR1/TIM1. IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1 is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions.

Published ahead of print on 17 January 2007.