Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease
Louise F. Risnes, Asbjørn Christophersen, Shiva Dahal-Koirala, Ralf S. Neumann, Geir K. Sandve, Vikas K. Sarna, Knut E.A. Lundin, Shuo-Wang Qiao, Ludvig M. Sollid
Louise F. Risnes, Asbjørn Christophersen, Shiva Dahal-Koirala, Ralf S. Neumann, Geir K. Sandve, Vikas K. Sarna, Knut E.A. Lundin, Shuo-Wang Qiao, Ludvig M. Sollid
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Research Article Autoimmunity Immunology

Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease

Abstract

Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer–sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-α, TCR-β, or paired TCR-αβ amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target.

Authors

Louise F. Risnes, Asbjørn Christophersen, Shiva Dahal-Koirala, Ralf S. Neumann, Geir K. Sandve, Vikas K. Sarna, Knut E.A. Lundin, Shuo-Wang Qiao, Ludvig M. Sollid

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Figure 2

Preexisting T cell clonotypes expand and dominate during and after gluten-challenge response.

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Preexisting T cell clonotypes expand and dominate during and after glute...
(A) Frequency of CD4+ T cells binding to a pool of HLA-DQ:gluten tetramers in blood and duodenal biopsy samples from 7 patients during gluten challenge. Tem, effector-memory T cells. (B) Distribution of TCR-αβ clonotypes obtained by single-cell TCR sequencing of tetramer-binding T cells from the 2 patients who showed the most response. Data from the remaining 5 patients are shown in Supplemental Figure 3C and Supplemental Figure 4. The x axes denote the sampling time points baseline before challenge (B) and day 6 (D6), day 14, and day 28 after the initiation of gluten challenge. The y axes show the percentage share of each clonotype represented as stacked boxes. Only clonotypes observed in at least 2 cells are plotted, and the most dominant clonotypes are displayed as numbers within the boxes. The colored boxes represent the 3 most dominant clonotypes at day 6 that were also observed at other time points. The isolated and nonstacked colored boxes represent shared clonotypes with clonal size 1. The total numbers of clonotypes and cells in each sample are shown below each stacked bar. Reoccurrence of identical TCR clonotypes in different samples from patients CD1300 and CD442 is depicted in area-proportional Venn diagrams (C and D). (C) TCR-αβ clonotype data obtained by single-cell sequencing. (D) TCR-β clonotype data compiled from both single-cell and bulk sequencing. The dark red areas represent clonotypes that were observed both at baseline and at the latest time point. The percentages denote the proportion of these shared clonotypes (dark red areas) at the latest time points (black border). The light red areas represent all other clonotype overlaps. Asterisks show only single-cell data for day 28.