Preferential presentation of herpes simplex virus T-cell antigen by HLA DQA1*0501/DQB1*0201 in comparison to HLA DQA1*0201/DQB1*0201.
The HLA DQA1 locus is polymorphic. Haplotypes containing HLA DQA1*0501, but not HLA DQA1*0201, together with HLA DQB1*0201 are associated with Grave's disease and celiac sprue. In this report, we demonstrate a functional correlate of DQA1 polymorphism. T cells infiltrating a herpes simplex virus (HSV) lesion from a HLA DQ 2,7 individual yielded a virus-specific CD4+ clone restricted by DQ2. Presentation of viral peptide and protein segregated with DQA1 allele, because cell lines bearing DQA1*0501/DQB1*0201 heterodimers presented antigen in proliferation and cytotoxicity assays much more efficiently than cell lines bearing DQA1*0201/DQB1*0201. Binding of viral peptide to cell lines bearing DQA1*0201, in comparison to DQA1*0501, was only moderately reduced and may not explain this effect. Truncation and substitution analyses of peptide binding and T-cell activation were performed to determine which viral peptide residues contacting TCR might therefore be presented in an altered conformation by DQA1*0201/DQB1*0201. Residues 432, 435, 437, 438, and 440 (position P1, P4, P6, P7, and P9) contributed to DQ2 binding, whereas residues 431, 433, 434, and 436 (positions P 1, P2, P3, and P5) contributed to TCR contact. Differential presentation of peptide by HLA DQ2 heterodimers varying at the DQA1 locus may have relevance to host defense and the pathogenesis of HLA DQ2-associated autoimmune diseases.
Koelle
D M
DM
Department of Medicine, University of Washington, School of Medicine, Seattle, USA.
Johnson
M L
ML
Ekstrom
A N
AN
Byers
P
P
Kwok
W W
WW
D000483:Alleles; D000596:Amino Acids / Q000032:analysis; D017951:Antigen Presentation / Q000235:genetics*; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D017405:Herpes Simplex Virus Protein Vmw65 / Q000276:immunology / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D010455:Peptides / Q000032:analysis; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
D000596:Amino Acids; D000956:Antigens, Viral; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C057615:HLA-DQbeta antigen; D017405:Herpes Simplex Virus Protein Vmw65; D010455:Peptides; D011948:Receptors, Antigen, T-Cell