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We previously showed that Class II HLA molecules transmitted signals in antigen presentation, and cross-linking HLA-DQ induced the interleukin 10 (IL-10) response of monocytes via p38 mitogen-activated protein kinase (p38MAPK). In this study, cross-linking DQ of B cells led to the phosphorylation of Ser-255 of heat shock protein 90\u03b2 (Hsp90\u03b2). Hsp90 and casein kinase 2 (CK2), 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 cross-linking-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 immunoglobulin G4 (IgG4) levels. These observations shed light on the novel nonclassical function of HLA molecules.<\/jats:p>","DOI":"10.1093\/intimm\/dxag049","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:32:18Z","timestamp":1789673538000},"source":"Crossref","is-referenced-by-count":0,"title":["Polymorphic tail of HLA-DQ leads to the heterogeneous interleukin-10 response of antigen-presenting cells"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4810-1065","authenticated-orcid":false,"given":"Sho","family":"Matsushita","sequence":"first","affiliation":[{"name":"Integrated Research Administration Center, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Department of Microbiology, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Department of Respiratory Medicine, Saitama Medical University Hospital, Moroyama 3500495 ,","place":["Japan"]},{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Takagi","sequence":"additional","affiliation":[{"name":"Integrated Research Administration Center, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Department of Microbiology, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Department of Immunology, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieko","family":"Tokano","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"},{"name":"Department of Infectious Disease and Infection Control, Saitama Medical University Hospital , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Nakagome","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Saitama Medical University Hospital, Moroyama 3500495 ,","place":["Japan"]},{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Soma","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Saitama Medical University Hospital, Moroyama 3500495 ,","place":["Japan"]},{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Saitama Medical University Hospital, Moroyama 3500495 ,","place":["Japan"]},{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-4717","authenticated-orcid":false,"given":"Masaaki","family":"Kawano","sequence":"additional","affiliation":[{"name":"Allergy Center, Saitama Medical University Hospital , Moroyama 3500495, Japan"},{"name":"Department of Immunology, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"},{"name":"Division of Analytical Science, Biomedical Research Center, Faculty of Medicine, Saitama Medical University , Moroyama 3500495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"2026100613164364500_dxag049-B1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.immuni.2006.10.019","article-title":"Full activation of the T cell receptor requires both clustering and conformational changes at CD3","volume":"26","author":"Minguet","year":"2007","journal-title":"Immunity"},{"key":"2026100613164364500_dxag049-B2","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/327629a0","article-title":"Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes","volume":"327","author":"Cambier","year":"1987","journal-title":"Nature"},{"key":"2026100613164364500_dxag049-B3","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.4049\/jimmunol.144.10.3684","article-title":"The role of class II molecules in human B cell activation. 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