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Gluten‐specific CD4+ T cells being drivers of celiac disease (CeD) are obvious targets for immunotherapy. Little is known about how cell markers harnessed for T‐cell‐directed therapy can change with time and upon activation in CeD and other autoimmune conditions. In‐depth characterization of gluten‐specific CD4+ T cells and CeD‐associated (CD38+ and CD103+) CD8+ and γδ+ T cells in blood of treated CeD patients undergoing a 3 day gluten challenge is reported. The phenotypic profile of gluten‐specific cells changes profoundly with gluten exposure and the cells adopt the profile of gluten‐specific cells in untreated disease (CD147+, CD70+, programmed cell death protein 1 (PD‐1)+, inducible T‐cell costimulator (ICOS)+, CD28+, CD95+, CD38+, and CD161+), yet with some markers being unique for day 6 cells (C‐X‐C chemokine receptor type 6 (CXCR6), CD132, and CD147) and with integrin α4β7, C‐C motif chemokine receptor 9 (CCR9), and CXCR3 being expressed stably at baseline and day 6. Among gluten‐specific CD4+ T cells, 52% are CXCR5+ at baseline, perhaps indicative of germinal‐center reactions, while on day 6 all are CXCR5−. Strikingly, the phenotypic profile of gluten‐specific CD4+ T cells on day 6 largely overlaps with that of CeD‐associated (CD38+ and CD103+) CD8+ and γδ+ T cells. The antigen‐induced shift in phenotype of CD4+ T cells being shared with other disease‐associated T cells is relevant for development of T‐cell‐directed therapies. [ABSTRACT FROM AUTHOR]

In celiac disease (CeD), gluten activates adaptive immune cells that cause damage to the small intestinal mucosa. Histological evaluation of intestinal biopsies allows for grading of disease severity. CeD can effectively be treated with a life‐long gluten‐free diet. Gluten challenge of treated CeD patients is used to confirm diagnosis and to test drug efficacy in clinical trials, but patients respond with different magnitudes to the same gluten challenge. In this study of 19 well‐treated CeD patients, proteome analysis of total tissue or isolated epithelial cell compartment from formalin‐fixed paraffin embedded biopsies collected before and after 14‐day gluten challenge demonstrates that patients with strong mucosal response to challenge have signs of ongoing tissue inflammation already before challenge. This low‐level tissue inflammation at baseline is paralleled by increased gluten specific CD4+ T‐cell frequencies in the gut and presence of a low‐level blood inflammatory profile. Thus, apparently well‐treated CeD is frequently not entirely quiescent, with presence of low‐grade inflammation and antigluten immunity in the gut mucosa. Histology assessment alone appears insufficient to judge full recovery and gut mucosal healing of CeD patients. The findings raise a concern whether a seemingly proper gluten‐free diet is able to curb gut inflammation in all CeD patients. [ABSTRACT FROM AUTHOR]

Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T-Cell-Directed Therapies Grey background indicates time period of gluten ingestion. gl The authors apologize for any inconvenience caused. Median of symptoms expressed in a VAS score (maximal value 100 mm) for the categories Pain, Bloating, Flatulence, Nausea, Satisfaction with defecation and Total complaints and GSRS questionnaire for the categories Pain, Bloating, Constipation, Diarrhea and Satiety in total n = 17 celiac disease patients undergoing a 3-day gluten challenge. [Extracted from the article]