Circulating Cd103(+) Gamma Delta And Cd8(+) T Cells Are Clonally Shared With Tissue-Resident Intraepithelial Lymphocytes In Celiac Disease

Gut intraepithelial gamma delta and CD8(+) alpha beta T lymphocytes have been connected to celiac disease (CeD) pathogenesis. Based on the previous observation that activated (CD38(+)), gut-homing (CD103(+)) gamma delta and CD8(+) alpha beta 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(+)) gamma delta and CD8(+) alpha beta T cells, respectively, while 16 had increase in gluten-specific CD4(+) T cells. We obtained gamma delta and alpha beta 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 gamma delta and CD8(+) alpha beta T-cell clonotypes even prior to gluten challenge. In subjects with challenge-induced surge of gamma delta and/or CD8(+) alpha beta 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 gamma delta or CD8(+) alpha beta T-cell clonotypes that may not be specific for the gluten antigen.