High efficiency CD91- and LOX-1-mediated re-presentation of gp96-chaperoned peptides by MHC II molecules

Toyoshi Matsutake1, Tatsuya Sawamura2 and Pramod K. Srivastava1

1Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA

2Department of Vascular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan

Contributed by: PK Srivastava

Keywords: mice, immunization, heat shock proteins, peptides, cellular immunity


Exogenous antigens enter antigen-presenting cells through non-specific mechanisms and are presented by the MHC II molecules. We show here that antigens chaperoned by the heat shock protein gp96 enter dendritic cells and B cells through a specific, CD91- and LOX-1-mediated mechanism, and are presented by MHC II molecules, in addition to MHC I molecules as previously demonstrated. Receptor utilization results in high efficiency uptake such that antigen concentrations as low as 10-9 M, if chaperoned by gp96, lead to productive antigen presentation. Chaperoning by gp96 increases the efficiency of uptake over un-chaperoned peptides by up to two orders of magnitude. Consistent with these studies in vitro, immunization of mice with gp96-peptide complexes (containing 5 ng peptide) results in generation of a peptide-specific CD4+ T cell response. The high efficiency suggests a mechanism in which dendritic cells, exposed in vivo to heat shock protein-chaperoned peptides liberated by virus-infected host cells or by the lysis of infecting bacteria, may prime and expand specific CD4+ responses.