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© The Rockefeller University Press, 0021-9525/2002/9/1277 $5.00
The Journal of Cell Biology, Volume 158, Number 7, September 30, 2002 1277-1285

CD40, an extracellular receptor for binding and uptake of Hsp70–peptide complexes

¹ Biochemie Zentrum Heidelberg (BZH), D-69120 Heidelberg, Germany
² Department of Biochemistry, Max-Planck Institut für Biochemie, D-82152 Martinsreid, Germany

Address correspondence to Felix Wieland, Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Tel.: 49-6221-544150. Fax: 49-6221-544366. E-mail: felix.wieland{at}urz.uni-heidelberg.de

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 NH₂-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.

Key Words: heat shock protein receptor; immune response; cross priming; co-chaperone; CD40; antigen-presenting cell

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