Adjuvanticity of alpha(2)-macroglobulin, an independent ligand for the heat shock protein receptor CD91

We recently have identified CD91 as a receptor for the heat shock protein g p96. CD91 was identified initially as a receptor for alpha (2)-macroglobuli n (alpha M-2). Gp96 and alpha M-2 are both ligands for CD91. Because gp96-c haperoned peptides can prime CD8(+) T cell responses and are re-presented b y APCs, we tested alpha M-2 for similar properties. Our studies show that a lpha M-2 binds peptides in vitro and that the peptides, chaperoned by alpha M-2, efficiently prime peptide-specific CD8(+) T cell responses in mice im munized with alpha M-2-peptide complexes. Furthermore, peptides chaperoned by alpha M-2 like those chaperoned by gp96, can be re-presented by CD91(+) APCs on their MHC I molecules. These studies demonstrate that alpha M-2 mol ecules, like the heat shock protein molecules, are T cell adjuvants that ca n channel exogenous Ags into the endogenous pathway of Ag presentaion. The remarkable similarities between an intracellular chaperone and an extracell ular serum chaperone may have interesting physiological ramifications.