SummaryCeliac disease (CD) is most probably an immunological disease, precipitated in susceptible individuals by ingestion of wheat gliadin and related proteins from other cereals. The disease shows a strong human HLA association predominantly to the c/s or trans encoded HLA-DQ(o~I*O5OI,fll*0201) (DQ2) heterodimer. T cell recognition of gliadin presented by this DQ heterodimer may thus be of immunopathogenic importance in CD. We therefore challenged small intestinal biopsies from adult CD patients on a gluten-free diet in vitro with gluten (containing both gliadin and other wheat proteins), and isolated activated CD25 + T cells. Polyclonal T cell lines and a panel of T cell clones recognizing gluten were established. They recognized the gliadin moiety of gluten, but not proteins from other cereals. Inhibition studies with anti-HLA antibodies demonstrated predominant antigen presentation by HLA-DQ molecules. The main antigen-presenting molecule was established to be the CD-associated DQ(oel*0501, fl1"0201) heterodimer. The gluten-reactive T cell clones were CD4 +, CD8-, and carried diverse combinations of T cell receptor (TCR) Vc~ and Vfl chains. The findings suggest preferential mucosal presentation of gluten-derived peptides by HLA-DQ(c~I*OSO1,BI*0201) in CD, which may explain the HLA association.