graduate research assistant Georgia State Univ. Atlanta, Georgia, United States
Disclosure(s):
Fatemeh Mousavinasab, PhD: No financial relationships to disclose
Introduction/Rationale: Celiac disease (CeD) is an immune-mediated enteropathy triggered by CD4⁺ T-cell recognition of gluten-derived peptides presented by HLA-DQ8, leading to chronic intestinal inflammation. Although regulatory T cells (Tregs) are central to mucosal tolerance, the relative contributions of thymus-derived Tregs (tTregs) versus peripherally induced Tregs (pTregs) remain unresolved. Here, we define the role of pTregs in gluten-driven inflammation using a transgenic mouse model that separates tTreg and pTreg function in the context of HLA-DQ8–restricted antigen presentation.
Methods: Mice: HLA-DQ8/I-Aᵇ knockout (Ab⁻/⁻) mice were bred with CNS1-deficient (CNS⁻/⁻) mice, which lack pTreg generation, and Foxp3-GFP reporter mice. Four groups were defined by genotype (CNS⁻/⁻ vs. CNS⁺/⁺) and diet (gluten-free diet [GFD] vs. regular chow). Experimental designs: (1) Adoptive transfer of CD4⁺ T cells into TCRα⁻/⁻ recipients, followed by a diet switch. (2) Direct switch from GFD to regular chow. (3) Mucosal adjuvant model using cholera toxin (±gluten) with diet change. Readouts: Body weight and fecal lipocalin-2 were tracked as clinical and inflammatory markers. Immune profiling via flow cytometry was done on mesenteric lymph nodes, lamina propria, and intraepithelial lymphocytes (IELs).
Results: Across all study arms, CNS⁻/⁻ mice maintained on regular chow developed significant weight loss and elevated fecal lipocalin-2, indicating intestinal inflammation. Flow cytometry revealed increased frequencies of activated lymphocytes in CNS⁻/⁻ mice on regular chow compared with all other groups in different organs.
Conclusion: This novel mouse model provides a robust platform for studying the role of pTregs in gluten-induced tolerance and celiac disease–associated inflammation. The findings underscore the importance of pTregs in maintaining intestinal immune homeostasis and offer a valuable tool for future mechanistic and therapeutic investigations
