nvironmental enteric dysfunction induces regulatory T cells that inhibit local CD4+T cell responses and impair oral vaccine efficac

Author(s):Show less -

Bhattacharjee, Amrita ^[1] ; Burr, Ansen H. P. ^{[1, 2]} ; Overacre-Delgoffe, Abigail E. ^[1] ; Tometich, Justin T. ^[1] ; Yang, Deyi ^{[1, 3]} ; Huckestein, Brydie R. ^[2] ; Linehan, Jonathan L. ^{[4, 5]} ; Spencer, Sean P. ^{[5, 6]} ; Hall, Jason A. ^{[5, 7]} ; Harrison, Oliver J. ^{[5, 8]} ; da Fonseca, Denise Morais ^{[9, 5]} ; Norton, Elizabeth B. ^[10] ; Belkaid, Yasmine ^[5] ; Hand, Timothy W. ^{[1, 2]}

Affiliation

^[1] Univ Pittsburgh, UPMC Childrens Hosp Pittsburgh, RK Mellon Inst Pediat Res, Pediat Dept, Pittsburgh, PA 15224 - USA

^[2] Univ Pittsburgh, Sch Med, Dept Immunol, Program Microbiol & Immunol, Pittsburgh, PA 15261 - USA

^[3] Cent South Univ, Xiangya Sch Med, Changsha - Peoples R China

^[4] Genentech Inc, San Francisco, CA 94080 - USA

^[5] NIAID, Metaorganism Immun Sect, Lab Immune Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[6] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Palo Alto, CA 94304 - USA

^[7] ArsenalBio Inc, San Francisco, CA - USA

^[8] Benaroya Res Inst, Seattle, WA - USA

^[9] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[10] Tulane Univ, Sch Med, Dept Microbiol & Immunol, 1430 Tulane Ave, New Orleans, LA 70112 - USA

• Document type: Journal article
• Source: IMMUNITY; v. 54, n. 8, p. 1745+, AUG 10 2021.
• Web of Science Citations: 3

Abstract

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)

• FAPESP's process: 15/25364-0 - Impact of infection-induced immunological scarring on the long-term host metabolic homeostasis
• Grantee: Denise Morais da Fonseca
• Support Opportunities: Research Grants - Young Investigators Grants