Immune tolerance of food is mediated by layers of CD4+ T cell dysfunction

Research output: Contribution to journalArticlepeer-review

Abstract

Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food1,2. This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4+ T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut–liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4+ naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it.

Original languageEnglish (US)
Pages (from-to)762-768
Number of pages7
JournalNature
Volume607
Issue number7920
DOIs
StatePublished - Jul 28 2022

Bibliographical note

Funding Information:
We acknowledge J. Walter and C. Elwood for help with maintaining mice and the University of Minnesota Flow Cytometry Resource for maintenance of flow cytometers used in these studies. This work was supported by the NIH grant P01 AI035296 and R01 AI27998.

Funding Information:
We acknowledge J. Walter and C. Elwood for help with maintaining mice and the University of Minnesota Flow Cytometry Resource for maintenance of flow cytometers used in these studies. This work was supported by the NIH grant P01 AI035296 and R01 AI27998.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article

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