Determinants of gliadin-specific T cell selection in celiac disease.

Journal of immunology (Baltimore, Md. : 1950) 2015 Jun 15

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In HLA-DQ8-associated celiac disease (CD), the pathogenic T cell response is directed toward an immunodominant α-gliadin-derived peptide (DQ8-glia-α1). However, our knowledge of TCR gene usage within the primary intestinal tissue of HLA-DQ8 (+) CD patients is limited. We identified two populations of HLA-DQ8-glia-α1 tetramer(+) CD4(+) T cells that were essentially undetectable in biopsy samples from patients on a gluten-free diet but expanded rapidly and specifically after antigenic stimulation. Distinguished by expression of TRBV9, both T cell populations displayed biased clonotypic repertoires and reacted similarly against HLA-DQ8-glia-α1. In particular, TRBV9 paired most often with TRAV26-2, whereas the majority of TRBV9(-) TCRs used TRBV6-1 with no clear TRAV gene preference. Strikingly, both tetramer(+)/TRBV9(+) and tetramer(+)/TRBV9(-) T cells possessed a non-germline-encoded arginine residue in their CDR3α and CDR3β loops, respectively. Comparison of the crystal structures of three TRBV9(+) TCRs and a TRBV9(-) TCR revealed that, as a result of distinct TCR docking modes, the HLA-DQ8-glia-α1 contacts mediated by the CDR3-encoded arginine were almost identical between TRBV9(+) and TRBV9(-) TCRs. In all cases, this interaction centered on two hydrogen bonds with a specific serine residue in the bound peptide. Replacement of serine with alanine at this position abrogated TRBV9(+) and TRBV9(-) clonal T cell proliferation in response to HLA-DQ8-glia-α1. Gluten-specific memory CD4(+) T cells with structurally and functionally conserved TCRs therefore predominate in the disease-affected tissue of patients with HLA-DQ8-mediated CD. Copyright © 2015 by The American Association of Immunologists, Inc.

Citation

Jan Petersen, Jeroen van Bergen, Khai Lee Loh, Yvonne Kooy-Winkelaar, Dennis X Beringer, Allan Thompson, Sjoerd F Bakker, Chris J J Mulder, Kristin Ladell, James E McLaren, David A Price, Jamie Rossjohn, Hugh H Reid, Frits Koning. Determinants of gliadin-specific T cell selection in celiac disease. Journal of immunology (Baltimore, Md. : 1950). 2015 Jun 15;194(12):6112-22