Burr, Ansen H. P.
Overacre-Delgoffe, Abigail E.
Tometich, Justin T.
Huckestein, Brydie R.
Linehan, Jonathan L.
Spencer, Sean P.
Hall, Jason A.
Harrison, Oliver J.
da Fonseca, Denise Morais
Norton, Elizabeth B.
Hand, Timothy W.
Total Authors: 14
 Univ Pittsburgh, UPMC Childrens Hosp Pittsburgh, RK Mellon Inst Pediat Res, Pediat Dept, Pittsburgh, PA 15224 - USA
 Univ Pittsburgh, Sch Med, Dept Immunol, Program Microbiol & Immunol, Pittsburgh, PA 15261 - USA
 Cent South Univ, Xiangya Sch Med, Changsha - Peoples R China
 Stanford Univ, Sch Med, Dept Microbiol & Immunol, Palo Alto, CA 94304 - USA
 ArsenalBio Inc, San Francisco, CA - USA
 Benaroya Res Inst, Seattle, WA - USA
 Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil
 Tulane Univ, Sch Med, Dept Microbiol & Immunol, 1430 Tulane Ave, New Orleans, LA 70112 - USA
Total Affiliations: 10
AUG 10 2021.
Web of Science Citations:
Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4(+) T cells in these mice revealed impaired CD4(+) T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident ROR gamma T(+)FOXP3(+) regulatory T (Treg) cells. Targeted deletion of ROR gamma T from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of ROR gamma T(+)FOXP3(+) Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how ROR gamma T(+)FOXP3(+) Treg cells can regulate intestinal immunity while leaving systemic responses intact. (AU)