Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy.

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 RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+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 RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

• Authors: Amrita Bhattacharjee, Ansen H P Burr, Abigail E Overacre-Delgoffe, Justin T Tometich, Deyi Yang, Brydie R Huckestein, Jonathan L Linehan, Sean P Spencer, Jason A Hall, Oliver J Harrison, Denise Morais da Fonseca, Elizabeth B Norton, Yasmine Belkaid, Timothy W Hand
• Journal: Immunity (Immunity) Vol. 54 Issue 8 Pg. 1745-1757.e7 (08 10 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 34348118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Bacterial Toxins
• Escherichia coli Vaccines
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Nuclear Receptor Subfamily 1, Group F, Member 3

Topics

• Administration, Oral
• Animals
• Bacterial Toxins (immunology)
• Cell Line
• Disease Models, Animal
• Drosophila
• Escherichia coli (immunology)
• Escherichia coli Vaccines (immunology)
• Female
• Forkhead Transcription Factors (metabolism)
• Gastrointestinal Diseases (immunology, microbiology, pathology)
• Intestine, Small (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nuclear Receptor Subfamily 1, Group F, Member 3 (metabolism)
• T-Lymphocytes, Regulatory (immunology)
• Vaccination