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Adjuvanticity of ₂-Macroglobulin, an Independent Ligand for the Heat Shock Protein Receptor CD91¹

Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030

We recently have identified CD91 as a receptor for the heat shock protein gp96. CD91 was identified initially as a receptor for ₂-macroglobulin (₂M). Gp96 and ₂M are both ligands for CD91. Because gp96-chaperoned peptides can prime CD8⁺ T cell responses and are re-presented by APCs, we tested ₂M for similar properties. Our studies show that ₂M binds peptides in vitro and that the peptides, chaperoned by ₂M, efficiently prime peptide-specific CD8⁺ T cell responses in mice immunized with ₂M-peptide complexes. Furthermore, peptides chaperoned by ₂M, like those chaperoned by gp96, can be re-presented by CD91⁺ APCs on their MHC I molecules. These studies demonstrate that ₂M molecules, like the heat shock protein molecules, are T cell adjuvants that can channel exogenous Ags into the endogenous pathway of Ag presentaion. The remarkable similarities between an intracellular chaperone and an extracellular serum chaperone may have interesting physiological ramifications.

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