Gluten-free diet induces rapid changes in phenotype and survival properties of gluten-specific T cells in celiac disease.

BACKGROUND AND AIMS: The treatment of celiac disease (CeD) with gluten-free diet (GFD) normalizes gut inflammation and disease-specific antibodies. CeD patients have HLA-restricted, gluten-specific T cells persisting in the blood and gut even after decades of GFD, which are re-activated and disease driving upon gluten exposure. Our aim was to examine the transition of activated gluten-specific T cells into a pool of persisting memory T cells concurrent with normalization of clinically relevant biomarkers during the first year of treatment.

METHODS: We followed 17 CeD patients during their initial GFD year, leading to disease remission. We assessed activation and frequency of gluten-specific CD4+ blood and gut T cells with HLA-DQ2.5:gluten tetramers and flow cytometry, disease-specific serology, histology and symptom scores. We assessed gluten-specific blood T cells within the first three weeks of GFD in six patients and serology in additional nine patients.

RESULTS: Gluten-specific CD4+ T cells peaked in blood at day 14 while upregulating Bcl-2 and downregulating Ki-67, then decreased in frequency within 10 weeks of GFD. CD38, ICOS, HLA-DR and Ki-67 decreased in gluten-specific cells within three days. PD-1, CD39 and OX40 expression persisted even after 12 months. IgA-TG2 decreased significantly within four weeks.

CONCLUSION: GFD induces rapid changes in phenotype and number of gluten-specific CD4+ blood T cells, including a peak of non-proliferating, non-apoptotic cells at day 14. Subsequent alterations in T-cell phenotype associate with the quiescent but chronic nature of treated CeD. The rapid changes affecting gluten-specific T cells and disease-specific antibodies offer opportunities for clinical trials aiming at developing non-dietary treatments for newly diagnosed CeD patients.