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How T cells taste gluten in celiac disease

Nature Structural & Molecular Biology volume 21, pages 429–431 (2014)Cite this article

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Genome-wide association studies have identified genes encoding major histocompatibility (MHC) class II molecules as the single most important predisposing factor for autoimmunity. A new study provides atomic insight into how the antigen receptors of intestinal T cells recognize dietary gluten that drives celiac disease pathogenesis when bound to the MHC class II molecule HLA-DQ2.5, the major genetic risk factor of celiac disease.

Despite the identification of MHC class II molecules as critical predisposing factors for autoimmunity, understanding of why certain specific MHC associations drive particular organ-specific autoimmune disorders is still very poor. Celiac disease is an intestinal disorder caused by an inappropriate immune response to cereal gluten proteins in wheat, barley and rye. More than 99% of people with celiac disease express the MHC class II molecules HLA-DQ2.5, HLA-DQ8 or HLA-DQ2.2, with HLA-DQ2.5 being the major genetic risk factor present in 90% of patients. Despite being caused by exposure to an exogenous dietary antigen, celiac disease has key features of organ-specific autoimmune disorders, such as the presence of autoantibodies directed against tissue transglutaminase 2 and the selective destruction of surface intestinal epithelial cells1.

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Figure 1: Schematic representation of the TCR interactions with two immunodominant gluten epitopes bound to HLA-DQ2.5 (DQ2.5-glia-α2 and DQ2.5-glia-α1a) reported by Petersen et al.2.
Figure 2: The side chain of the glutamate at P4 in the DQ2.5-glia-α2 epitope forms a salt bridge to the side chain of Lys71β and a hydrogen bond to the side chain of Ser28β in the HLA-DQ2.5 molecule.

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Acknowledgements

The work was supported by grants from the US National Institutes of Health (RO1DK063158, RO1DK58727and P30DK42086) to B.J. and by grants from the Research Council of Norway, the European Research Council and the South-East Norway Regional Health Authority to L.M.S.

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Authors and Affiliations

  1. Bana Jabri is at the Department of Medicine, University of Chicago, Chicago, Illinois, USA.,

    Bana Jabri

  2. Xi Chen and Ludvig M. Sollid are at the Centre for Immune Regulation, University of Oslo, Oslo, Norway, and Oslo University Hospital–Rikshospitalet, Oslo, Norway.,

    Xi Chen & Ludvig M Sollid

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  1. Bana Jabri
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Correspondence to Bana Jabri or Ludvig M Sollid.

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Jabri, B., Chen, X. & Sollid, L. How T cells taste gluten in celiac disease. Nat Struct Mol Biol 21, 429–431 (2014). https://doi.org/10.1038/nsmb.2826

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