Human small intestine contains 2 functionally distinct regulatory T-cell subsets

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Regulatory T (Treg) CD4 cells in the mouse gut are crucial for immune tolerance to dietary antigens and microbiota.
• Limited data exists on the phenotype and function of Treg cells within the human gut.

Purpose of the Study:

• To comprehensively characterize Foxp3+ CD4 Treg cells in the human small intestine (SI).
• To compare Treg cells from normal SI, transplanted duodenal tissue, and celiac disease lesions.

Main Methods:

• Detailed immunophenotyping of Treg cells and conventional CD4 T cells from the human SI.
• Assessment of Treg cell suppressive activity and cytokine production.
• Analysis of Helios expression within Treg cell subsets.

Main Results:

• Human SI Treg cells (Foxp3+ CD4) were CD45RA-CD127-CTLA-4+ and suppressed T cell proliferation.
• Approximately 60% of Treg cells expressed Helios; Helios-negative Treg cells produced IL-17, IFN-γ, and IL-10 upon stimulation.
• Donor Helios-negative Treg cells persisted for at least 1 year post-transplantation.
• In active celiac disease, both Helios-negative and Helios-positive Treg cell subsets expanded significantly (5- to 10-fold) compared to normal SI (2% of CD4 T cells).

Conclusions:

• The human small intestine harbors two distinct subsets of Treg cells with differing phenotypes and functions.
• These Treg cell subsets are infrequent in healthy individuals but markedly increase during active celiac disease.