Circulating CD103+ γδ and CD8+ T cells are clonally shared with tissue-resident intraepithelial lymphocytes in celiac disease

Louise F Risnes, Linn M Eggesbø, Stephanie Zühlke, Shiva Dahal-Koirala, Ralf S Neumann, Knut E A Lundin, Asbjørn Christophersen, Ludvig M Sollid, Louise F Risnes, Linn M Eggesbø, Stephanie Zühlke, Shiva Dahal-Koirala, Ralf S Neumann, Knut E A Lundin, Asbjørn Christophersen, Ludvig M Sollid

Abstract

Gut intraepithelial γδ and CD8+ αβ T lymphocytes have been connected to celiac disease (CeD) pathogenesis. Based on the previous observation that activated (CD38+), gut-homing (CD103+) γδ and CD8+ αβ T cells increase in blood upon oral gluten challenge, we wanted to shed light on the pathogenic involvement of these T cells by examining the clonal relationship between cells of blood and gut during gluten exposure. Of 20 gluten-challenged CeD patients, 8 and 10 had increase in (CD38+CD103+) γδ and CD8+ αβ T cells, respectively, while 16 had increase in gluten-specific CD4+ T cells. We obtained γδ and αβ TCR sequences of >2500 single cells from blood and gut of 5 patients, before and during challenge. We observed extensive sharing between blood and gut γδ and CD8+ αβ T-cell clonotypes even prior to gluten challenge. In subjects with challenge-induced surge of γδ and/or CD8+ αβ T cells, as larger populations of cells analyzed, we observed more expanded clonotypes and clonal sharing, yet no discernible TCR similarities between expanded and/or shared clonotypes. Thus, CD4+ T cells appear to drive expansion of clonally diverse γδ or CD8+ αβ T-cell clonotypes that may not be specific for the gluten antigen.

Trial registration: ClinicalTrials.gov NCT00246415.

References

    1. Lebwohl, B., Sanders, D. S. & Green, P. H. R. Coeliac disease. Lancet 391, 70–81 (2018).
    1. Sollid, L. M. Molecular basis of celiac disease. Annu Rev. Immunol. 18, 53–81 (2000).
    1. Bodd, M. et al. Direct cloning and tetramer staining to measure the frequency of intestinal gluten-reactive T cells in celiac disease. Eur. J. Immunol. 43, 2605–2612 (2013).
    1. Risnes, L. F. et al. Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. J. Clin. Invest 128, 2642–2650 (2018).
    1. Lundin, K. E. et al. Gliadin-specific, HLA-DQ(α1*0501,β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187–196 (1993).
    1. Christophersen, A. et al. Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. U. Eur. Gastroenterol. J. 2, 268–278 (2014).
    1. Raki, M. et al. Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc. Natl Acad. Sci. USA 104, 2831–2836 (2007).
    1. Zuhlke, S. et al. CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease. U. Eur. Gastroenterol. J. 7, 1337–1344 (2019).
    1. Anderson, R. P., Degano, P., Godkin, A. J., Jewell, D. P. & Hill, A. V. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat. Med. 6, 337–342 (2000).
    1. Han, A. et al. Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proc. Natl Acad. Sci. USA 110, 13073–13078 (2013).
    1. Mazzarella, G. et al. Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis. Gastroenterology 134, 1017–1027 (2008).
    1. Picascia, S. et al. Gliadin-specific CD8+ T cell responses restricted by HLA Class I A*0101 and B*0801 molecules in celiac disease patients. J. Immunol. 198, 1838–1845 (2017).
    1. Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366 (2004).
    1. Hüe, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377 (2004).
    1. Meresse, B. et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J. Exp. Med. 203, 1343–1355 (2006).
    1. Sarna, V. K. et al. HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge. Gut 67, 1606–1613 (2018).
    1. Eggesbo, L. M. et al. Single-cell TCR sequencing of gut intraepithelial γδ T cells reveals a vast and diverse repertoire in celiac disease. Mucosal Immunol. 13, 313–321 (2020).
    1. Jabri, B. et al. TCR specificity dictates CD94/NKG2A expression by human CTL. Immunity 17, 487–499 (2002).
    1. Mayassi, T. et al. Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease. Cell 176, 967–981.e919 (2019).
    1. Lopez-Palacios, N. et al. Evaluation of T cells in blood after a short gluten challenge for coeliac disease diagnosis. Dig. Liver Dis. 50, 1183–1188 (2018).
    1. Sollid, L. M. & Thorsby, E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology 105, 910–922 (1993).
    1. Bhagat, G. et al. Small intestinal CD8+TCRγδ+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Invest 118, 281–293 (2008).
    1. Jarry, A., Cerf-Bensussan, N., Brousse, N., Selz, F. & Guy-Grand, D. Subsets of CD3+ (T cell receptor α/β or γ/δ) and CD3− lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur. J. Immunol. 20, 1097–1103 (1990).
    1. Balk, S. P. et al. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science 253, 1411–1415 (1991).
    1. Kerckhove, C. Van et al. Oligoclonality of human intestinal intraepithelial T cells. J. Exp. Med. 175, 57–63 (1992).
    1. Fonseca, R. et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat. Immunol. 21, 412–421 (2020).
    1. Vander, J. A. et al. pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30, 1930–1932 (2014).

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