Physiological-Range Temperature Changes Modulate Cognate Antigen Processing and Presentation Mediated by Lipid Raft-Restricted Ubiquitinated B Cell Receptor Molecules

Abstract

BCR-mediated Ag processing and presentation is critical to the initiation and control of a humoral immune response. Trafficking of internalized Ag-BCR complexes to intracellular Ag processing compartments is driven by ubiquitination of the cytoplasmic domain of the BCR. Using a biochemical approach, it is here established that ubiquitinated Ag-BCR complexes are formed via a signaling-dependent mechanism and restricted to plasma membrane lipid rafts. Because the structure of lipid rafts is temperature sensitive, the impact of physiological-range temperature changes (PRTCs; 33-39°C) on lipid raft-dependent and -independent BCR functions was investigated. Whereas the kinetics of lipid raft-independent BCR internalization is unaffected by temperature changes within this range, raft-dependent BCR signaling and ubiquitination as well as BCR-mediated Ag processing are significantly affected. The extent and duration of Ag-BCR ubiquitination is increased and prolonged at 37-39°C (normal to febrile temperature) compared with that at 33°C (peripheral body temperature). As might be expected, increased temperature also accelerates the overall kinetics of Ag-BCR degradation. Notably, at 33°C the expression of peptide-MHC class II complexes derived from the BCR-mediated processing of cognate Ag is profoundly slowed, whereas the kinetics of expression of peptide-MHC class II complexes derived from fluid-phase Ag processing remains unchanged. These results establish the effect of PRTCs on multiple lipid raft-dependent BCR functions including the processing and presentation of cognate Ag, suggesting one mechanism by which PRTCs, such as fever, may impact the initiation and/or maturation of a humoral immune response.