MHC class II structural requirements for the association with Igα/β, and signaling of calcium mobilization and cell death

Emerging evidence indicates that in addition to their well-characterized role in antigen presentation, MHC II molecules transmit signals that induce death of APCs. Appropriately timed APC death is important for prevention of autoimmunity. Though the exact mechanism of MHC II-mediated cell death signaling is unknown, the response appears independent of caspase activation and does not involve Fas–FasL interaction. Here we investigated MHC II structural requirements for mediation of cell death signaling in a murine B cell lymphoma. We found that neither the transmembrane spanning regions nor the cytoplasmic tails of MHC II, which are required for MHC II-mediated cAMP production and PKC activation, are required for the death response. However, mutations in the connecting peptide region of MHC II α chain (αCP), but not the β chain (βCP), resulted in significant impairment of the death response. The αCP mutant was also unable to mediate calcium mobilization responses, and did not associate with Igα/β. Knock-down of Igβ by shRNA eliminated the MHC II-mediated calcium response but not cell death. We propose that MHC II mediates cell death signaling via association with an undefined cell surface protein(s), whose interaction is partially dependent on αCP region.