The human small intestine contains two functionally distinct regulatory T-cell subsets

J Allergy Clin Immunol. 2023 Mar 7;S0091-6749(23)00290-7. doi: 10.1016/j.jaci.2023.02.030. Online ahead of print.


Background: Regulatory CD4 T cells (Tregs) in the mice gut are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and members of the microbiota. However, information about the phenotype and function of Tregs in the human gut is limited.

Objective: Here, we performed a detailed characterization of Foxp3+ CD4 Tregs in human normal small intestine (SI) as well as from transplanted duodenum and celiac disease lesions.

Methods: Tregs and conventional CD4 T cells derived from SI were subjected to extensive immunophenotyping and their suppressive activity and ability to produce cytokines were assessed.

Results: SI Foxp3+ CD4 T cells were CD45RA- CD127- CTLA-4+ and suppressed proliferation of autologous T cells. Approximately 60% of the Tregs expressed the transcription factor Helios. When stimulated, Helios- Tregs produced IL-17, IFN-γ and IL-10, whereas Helios+ Tregs produced very low levels of these cytokines. By sampling mucosal tissue from transplanted human duodenum we demonstrated that donor Helios- Tregs persisted for at least 1 year post-transplantation. In normal SI, Foxp3+ Tregs constituted only 2% of all CD4 T cells, while in active celiac disease both Helios- and Helios+ subsets expanded 5-10-fold.

Conclusion: The SI contains two subsets of Tregs with different phenotypes and functional capacities. Both subsets are scarce in the healthy gut but increase dramatically in active celiac disease.

Keywords: CD4 T cells; Foxp3; Helios; celiac disease; human small intestine; regulatory T cells (Tregs); transplantation.