MHC class II conformers drive differential B cell activation

Abstract MHC class II molecules present exogenous antigen-derived peptides to CD4 T cells to elicit T cell-based help/regulation. While these peptides represent a robust source of heterogeneity, the class II molecules themselves are also heterogeneous. MHC class II molecules exist in two distinct conformational states, based on alternative pairing and differential cholesterol binding of the molecule’s α and β chain’s transmembrane domains. What have been termed “M2 paired” class II (M2 class II) represents the majority of cell surface class II, whereas M1 paired class II (M1 class II) is a smaller fraction of surface molecules. However, M1 class II is enriched in “lipid raft” membrane domains, is highly stimulatory for CD4 T cells and is selectively linked to B cell activation signaling pathways. Moreover, in B lymphocytes M1 class II selectively associates with intracellular antigen-B cell receptor (BCR) complexes and is selectively loaded with peptide derived from the processing of BCR-bound cognate antigen. In contrast, peptides from non-cognate antigen internalized by fluid-phase endocytosis (as would happen for self-antigens) is loaded onto both M1 and M2 class II. Here, we show that while selective engagement of M1 class II drives B cell calcium signaling (an activation event), co-engagement of M1 and M2 class II allows an M2 class II-associated inhibitory activity to block M1 class II signaling. These findings provide new insight into the molecular mechanisms of MHC class II signaling by revealing the distinct signaling properties of M1 and M2 class II. The results also suggest a B cell-intrinsic mechanism by which T cell recognition of M1 vs. M2 peptide-class II complexes could regulate B cell activation via differential class II signaling.