Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease.


Gabriela Rios Martini, Ekaterina Tikhonova, Elisa Rosati, Meghan Bialt DeCelie, Laura Katharina Sievers, Florian Tran, Matthias Lessing, Arne Bergfeld, Sophia Hinz, Susanna Nikolaus, Julia Kümpers, Anna Matysiak, Philipp Hofmann, Carina Saggau, Stephan Schneiders, Ann-Kristin Kamps, Gunnar Jacobs, Wolfgang Lieb, Jochen Maul, Britta Siegmund, Barbara Seegers, Holger Hinrichsen, Hans-Heinrich Oberg, Daniela Wesch, Stefan Bereswill, Markus M Heimesaat, Jan Rupp, Olaf Kniemeyer, Axel A Brakhage, Sascha Brunke, Bernhard Hube, Konrad Aden, Andre Franke, Iliyan D Iliev, Alexander Scheffold, Stefan Schreiber, Petra Bacher

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Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn’s disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic T helper cell (TH1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4+ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4+ T cell responses in patients with CD.