Sequestration of gut pathobionts in intraluminal casts, a mechanism to avoid dysregulated T cell activation by pathobionts

Martina Sassone-Corsi, Shalhevet Azriel, Ariel Simon, Deepshika Ramanan, Adriana Ortiz-Lopez, Felicia Chen, Nissan Yissachar, Diane Mathis, Christophe Benoist

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

T cells that express the transcription factor RORγ, regulatory (Treg), or conventional (Th17) are strongly influenced by intestinal symbionts. In a genetic approach to identify mechanisms underlying this influence, we performed a screen for microbial genes implicated, in germfree mice monocolonized with Escherichia coli Nissle. The loss of capsule-synthesis genes impaired clonal expansion and differentiation of intestinal RORγ+ T cells. Mechanistic exploration revealed that the capsule-less mutants remained able to induce species-specific immunoglobulin A (IgA) and were highly IgA-coated. They could still trigger myeloid cells, and more effectively damaged epithelial cells in vitro. Unlike wild-type microbes, capsule-less mutants were mostly engulfed in intraluminal casts, large agglomerates composed of myeloid cells extravasated into the gut lumen. We speculate that sequestration in luminal casts of potentially harmful microbes, favored by IgA binding, reduces the immune system’s actual exposure, preserving host–microbe equilibrium. The variable immunostimulation by microbes that has been charted in recent years may not solely be conditioned by triggering molecules or metabolites but also by physical limits to immune system exposure.

Original languageEnglish
Article numbere2209624119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number41
DOIs
StatePublished - 11 Oct 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.

Funding

B. Vijaykumar, and N. Patel for help with computational analyses, T.B. Yanortsonag for mice, and P. Montero Llopis and O. Yaghi for confocal imaging advice and assistance. This work was supported by grants AI125603 and AI150686 from the National Institutes of Health (to C.B. and D.M.), grant 3114831 from the Israel Science Foundation (to N.Y.), grant 8165162 from the Broad-ISF exchange (to N.Y., C.B., and D.M.), and in part by a Sponsred Research Agreement from Evelo Biosciences. M.S.C. was a Cancer Research Irvington Fellow.

FundersFunder number
Evelo Biosciences
National Institutes of Health3114831
National Institute of Allergy and Infectious DiseasesR01AI150686
Israel Science Foundation8165162

    Keywords

    • CD4 T cell
    • IgA
    • capsule
    • genetic screen
    • gut

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