Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T-Cell-Directed Therapies

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.