J Cell Biol 2002 Sep 30;158(7):1277-85
Becker T, Hartl FU, Wieland F.
Biochemie Zentrum Heidelberg (BZH), D-69120 Heidelberg, Germany. Department of Biochemistry, Max-Planck Institut fur Biochemie, D-82152 Martinsreid, Germany.
Tumor and viral antigens elicit a potent immune response by heat shock protein-dependent uptake of antigenic peptide with subsequent presentation by MHC I.
Receptors on antigen-presenting cells that specifically bind and internalize a heat shock protein-peptide complex have not yet been identified.
Here, we show that cells expressing CD40, a cell surface protein crucial for B cell function and autoimmunity, specifically bind and internalize human Hsp70 with bound peptide.
Binding of Hsp70-peptide complex to the exoplasmic domain of CD40 is mediated by the NH(2)-terminal nucleotide-binding domain of Hsp70 in its ADP state.
The Hsp70 cochaperone Hip, but not the bacterial Hsp70 homologue DnaK, competes formation of the Hsp70-CD40 complex.
Binding of Hsp70-ADP to CD40 is strongly increased in the presence of Hsp70 peptide substrate, and induces signaling via p38.
We suggest that CD40 is a cochaperone-like receptor mediating the uptake of exogenous Hsp70-peptide complexes by macrophages and dendritic cells.