Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, α-gliadin AJ133612 and γ-gliadin M36999. For α-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For γ-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some γ-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.
Stig Tollefsen, Helene Arentz-Hansen, Burkhard Fleckenstein, Øyvind Molberg, Melinda Ráki, William W. Kwok, Günther Jung, Knut E.A. Lundin, Ludvig M. Sollid
T cell lines derived from biopsy specimens of 3 different patients stimulated with chymotrypsin-treated recombinant AJ133612 α-gliadin were tested against the panel of TG2-treated AJ133612 α-gliadin peptides as in Figure