title: Type 1 diabetes associated HLA-DQ2 and DQ8 molecules are relatively resistant to HLA-DM mediated release of invariant chain-derived CLIP peptides.
abstract: HLA-DM is essential for editing peptides bound to MHC class II, thus influencing the repertoire of peptides mediating selection and activation of CD4(+) T cells. Individuals expressing HLA-DQ2 or DQ8, and DQ2/8 trans-dimers, have elevated risk for type 1 diabetes (T1D). Cells coexpressing DM with these DQ molecules were observed to express elevated levels of CLIP (Class II associated invariant chain peptide). Relative resistance to DM-mediated editing of CLIP was further confirmed by HPLC-MS/MS analysis of eluted peptides, which also demonstrated peptides from known T1D-associated autoantigens, including a shared epitope from ZnT8 that is presented by all four major T1D-susceptible DQ molecules. Assays with purified recombinant soluble proteins confirmed that DQ2-CLIP complexes are highly resistant to DM editing, whereas DQ8-CLIP is partially sensitive to DM, but with an apparent reduction in catalytic potency. DM sensitivity was enhanced in mutant DQ8 molecules with disruption of hydrogen bonds that stabilize DQ8 near the DM-binding region. Our findings show that T1D-susceptible DQ2 and DQ8 share significant resistance to DM editing, compared with control DQ molecules. The relative resistance of the T1D-susceptible DQ molecules to DM editing and preferential presentation of T1D-associated autoantigenic peptides may contribute to the pathogenesis of T1D.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Reyes-Vargas
authors.affiliation: ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Hernando
authors.initials: H
authors.lastname: Escobar
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Brant
authors.initials: B
authors.lastname: Rudd
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Rockwood
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Delgado
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Jensen
mesh_terms: D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D057809:HEK293 Cells; D006681:HLA-D Antigens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D000949:Histocompatibility Antigens Class II; C045084:invariant chain
keywords: Antigen presentation; HLA-DM; HLA-DQ; Invariant chain-derived CLIP peptides; Type 1 diabetes