B cell MHC class II signaling: A story of life and death

MHC class II regulates B cell activation, proliferation, and differentiation during cognate B cell-T cell interaction. This is, in part, due to the MHC class II signaling in B cells. Activation of MHC Class II in human B cells or “primed” murine B cells leads to tyrosine phosphorylation, calcium mobilization, AKT, ERK, JNK activation. In addition, crosslinking MHC class II with monoclonal Abs kill malignant human B cells. Several humanized anti-HLA-DR/MHC class II monoclonal Abs entered clinical trials for lymphoma/leukemia and MHC class II-expressing melanomas. Mechanistically, MHC class II is associated with a wealth of transmembrane proteins including the B cell-specific signaling proteins CD79a/b, CD19 and a group of four-transmembrane proteins including tetraspanins and the apoptotic protein MPYS/STING. Furthermore, MHC class II signals are compartmentalized in the tetraspanin-enriched microdomains. In this review, we discuss our current understanding of MHC class II signaling in B cells focusing on its physiological significance and the therapeutic potential.