Circulating gluten-specific FOXP3CD39 regulatory T cells have impaired suppressive function in patients with celiac disease.

BACKGROUND

Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood.

OBJECTIVE

We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) Treg cells.

METHODS

Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134).

RESULTS

Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 T cells were FOXP3CD39 Treg cells, which reside within the pool of memory CD4CD25CD127CD45RO Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3CD39 Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells.

CONCLUSION

This study provides the first estimation of FOXP3CD39 Treg cell frequency within circulating gluten-specific CD4 T cells after oral gluten challenge of patients with celiac disease. FOXP3CD39 Treg cells comprised a major proportion of all circulating gluten-specific CD4 T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis.