Polymorphic tail of HLA-DQ leads to the heterogeneous IL-10 response of antigen-presenting cells

The cytoplasmic tails of HLA molecules are heterogeneous and polymorphic in terms of length and amino-acid sequences. We previously showed that class II HLA molecules transmitted signals in antigen presentation, and cross-linking HLA-DQ induced the interleukin (IL)-10 response of monocytes via p38MAPK. In this study, cross-linking DQ of B cells led to the phosphorylation of Ser-255 of Hsp90β. Hsp90 and casein kinase (CK) 2 which can catalyze this phosphorylation pattern, were co-immunoprecipitated with DQ. The long-form DQ tail-derived peptides bound to CK2 protein with higher affinity. The crosslinking-induced IL-10 response was suppressed by specific inhibition of Hsp90 and CK2. Furthermore, anti-Hsp90 antibody co-immunoprecipitated mitogen-activated protein kinase kinase kinase 3 (MEKK3) and cerebral cavernous malformations 2 (CCM2), a scaffold for p38MAPK activation. Cross-linking DQ augmented co-immunoprecipitation of MEKK3 with CCM2, in an Hsp90-dependent manner. HLA-DQ thereby qualitatively controls heterogeneous immune responses through its polymorphic tails via HLA-kinase-chaperone-scaffold-MAPK cascade signaling into antigen-presenting cells. Subjects with long-form DQ alleles showed elevated plasma IL-10 and IgG4 levels. These observations shed light on the novel non-classical function of HLA molecules.