Gluten-specific T cells cross-react between HLA-DQ8 and the HLA-DQ2α/DQ8β transdimer.
Because susceptibility to celiac disease is associated strongly with HLA-DQ2 (DQA1*05/DQB1*02) and weakly with HLA-DQ8 (DQA1*03/DQB1*03), a subset of patients carries both HLA-DQ2 and HLA-DQ8. As a result, these patients may express two types of mixed HLA-DQ2/8 transdimers (encoded by DQA1*05/DQB1*03 and DQA1*03/DQB1*02) in addition to HLA-DQ2 and HLA-DQ8. Using T cells from a celiac disease patient expressing HLA-DQ8trans (encoded by DQA*0501/DQB*0302), but neither HLA-DQ2 nor HLA-DQ8, we demonstrate that this transdimer is expressed on the cell surface and can present multiple gluten peptides to T cell clones isolated from the duodenum of this patient. Furthermore, T cell clones derived from this patient and HLA-DQ2/8 heterozygous celiac disease patients respond to gluten peptides presented by HLA-DQ8trans, as well as HLA-DQ8, in a similar fashion. Finally, one gluten peptide is recognized better when presented by HLA-DQ8trans, which correlates with preferential binding of this peptide to HLA-DQ8trans. These results implicate HLA-DQ8trans in celiac disease pathogenesis and demonstrate extensive T cell cross-reactivity between HLA-DQ8 and HLA-DQ8trans. Because type 1 diabetes is strongly associated with the presence of HLA-DQ8trans, our findings may bear relevance to this disease as well.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Yvonne
Y
Kooy-Winkelaar
Menno
M
van Lummel
Antonis K
AK
Moustakas
Joachim
J
Schweizer
M Luisa
ML
Mearin
Chris J
CJ
Mulder
Bart O
BO
Roep
Jan W
JW
Drijfhout
George K
GK
Papadopoulos
Jeroen
J
van Bergen
Frits
F
Koning
D017951:Antigen Presentation / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D002999:Clone Cells; D003429:Cross Reactions / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005903:Gliadin / Q000276:immunology* / Q000378:metabolism*; D057809:HEK293 Cells; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D059866:HLA-DQ beta-Chains / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; C057615:HLA-DQbeta antigen; D005903:Gliadin