Intestinal Tr1 Cells Confer Protection against Colitis in the Absence of Foxp3+ Regulatory T Cell–Derived IL-10

Author:

Zhou Julie Y.1,Glendenning Leandre M.1ORCID,Cavanaugh Jill M.1,McNeer Sarah K.1ORCID,Goodman Wendy A.1,Cobb Brian A.1ORCID

Affiliation:

1. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH

Abstract

Abstract The intestinal mucosa is continually exposed to diverse microbial and dietary Ags, requiring coordinated efforts by specialized populations of regulatory T cells (Tregs) to maintain homeostasis. Suppressive mechanisms used by intestinal Tregs include the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. Defects in IL-10 signaling are associated with severe infantile enterocolitis in humans, and mice deficient in IL-10 or its receptors develop spontaneous colitis. To determine the requirement of Foxp3+ Treg-specific IL-10 for protection against colitis, we generated Foxp3-specific IL-10 knockout (KO) mice (IL-10 conditional KO [cKO] mice). Colonic Foxp3+ Tregs isolated from IL-10cKO mice showed impaired ex vivo suppressive function, although IL-10cKO mice maintained normal body weights and developed only mild inflammation over 30 wk of age (in contrast to severe colitis in global IL-10KO mice). Protection from colitis in IL-10cKO mice was associated with an expanded population of IL-10–producing type 1 Tregs (Tr1, CD4+Foxp3−) in the colonic lamina propria that produced more IL-10 on a per-cell basis compared with wild-type intestinal Tr1 cells. Collectively, our findings reveal a role for Tr1 cells in the gut, as they expand to fill a tolerogenic niche in conditions of suboptimal Foxp3+ Treg-mediated suppression and provide functional protection against experimental colitis.

Publisher

The American Association of Immunologists

Subject

Immunology and Allergy,General Medicine,Immunology

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