Role of Regulatory T Cells and Transglutaminase 2 Inhibitors in Celiac Disease: A Systematic Review

Celiac disease is an autoimmune disorder triggered by the ingestion of gluten in genetically predisposed individuals, leading to chronic intestinal inflammation and damage to the small intestinal lining (villus atrophy). While a strict gluten-free diet remains the primary treatment, emerging therapies targeting the immune response offer promising alternatives. This review focuses on the therapeutic potential of transglutaminase 2 (TG2) inhibitors, enzymes that, when overactive, contribute to immune system attacks on the gut, and regulatory T cells (Tregs), specialized immune cells that help calm down excessive immune reactions. This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Literature was searched across PubMed, Embase, and the Cochrane Library using both text terms and controlled vocabulary with Boolean operators ("AND," "OR"). We included full-text, open-access, English-language articles published between 2005 and 2025. The methodological quality of studies was assessed using the Mixed Methods Appraisal Tool. A total of 68 articles were initially identified. After screening and applying inclusion criteria, 14 studies were included in the final analysis. Among them, eight studies were rated as high quality (low risk of bias), while six were of moderate quality (uncertain risk of bias). TG2 inhibitors showed promising effects such as improved intestinal structure (villous architecture), reduced gastrointestinal symptoms, stabilized immune cell levels in the gut, and decreased activation of gluten-specific immune cells (CD4+ T cells). Treg therapies also demonstrated the ability to reduce inflammation by limiting the production of harmful immune signals such as interferon-gamma and interleukin-21. The findings highlight the therapeutic potential of TG2 inhibitors and Treg-based treatments in managing celiac disease by directly targeting the immune response. While preliminary results are promising, further clinical research is needed to confirm their effectiveness and safety for routine clinical use.