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

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.