We recently have identified CD91 as a receptor for the heat shock protein gp96. CD91 was identified initially as a receptor for α 2-macroglobulin (α 2 M). Gp96 and α 2 M are both ligands for CD91. Because gp96-chaperoned peptides can prime CD8+ T cell responses and are re-presented by APCs, we tested α 2 M for similar properties. Our studies show that α 2 M binds peptides in vitro and that the peptides, chaperoned by α 2 M, efficiently prime peptide-specific CD8+ T cell responses in mice immunized with α 2 M-peptide complexes. Furthermore, peptides chaperoned by α 2 M, like those chaperoned by gp96, can be re-presented by CD91+ APCs on their MHC I molecules. These studies demonstrate that α 2 M 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.