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1/ What is the physiological impact of dietary proteins on steady-state T cells? Nelson Vaz and Ana Faria, my undergrad mentors, wondered about this question for decades.
2/ Ainsley Lockhart, who recently brilliantly defended her thesis, took on this question and answered more comprehensively that I could ever dream when I started working on this question exactly 25 years ago.
3) Our new study used antigenically defined diets and gnotobiotic models to find individual contributions from food versus microbiota on the profile and T cell receptor repertoire of intestinal CD4+ T cells.
4/ Our study found that dietary proteins contribute to the accumulation and clonal selection of antigen-experienced CD4+ T cells in the intestinal epithelium, imprinting a tissue-specific transcriptional program on both conventional and regulatory CD4+ T cells.
5/ These observations inform about the antigen sources of CD4 T cell adaptation to the gut epithelium, topic covered by the lab for over a decade (see https://www.nature.com/articles/ni.2518)
6/ This tissue specialized transcriptional program includes cytotoxic genes on both conventional and regulatory CD4+ T cells (Tregs), also previously addressed by the lab (https://www.science.org/doi/10.1126/science.aaf3892?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed, or https://www.nature.com/articles/s41590-021-00883-8)
7/ Such steady-state CD4+ T cell response to food was disrupted by an inflammatory challenge, and protection against food allergy via previous ingestion of the protein (oral tolerance) was associated with Treg clonal expansion and decreased pro-inflammatory gene expression.
8/ The study also identified both steady-state epithelium-adapted CD4+ T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.
10/ Thanks to everyone involved in this 25 year-old project, particularly Ainsley Lockhart, Aubrey Reed, Tiago Castro, Calvin Herman, Ciça Canesso and all Mucida lab members, particularly Roham Parsa, who developed the fate-mapping model used in collaboration with the Nussenzweig lab.
This study is out today, and is open access:
https://rupress.org/jem/article/220/8/e20221816/214115/Dietary-protein-shapes-the-profile-and-repertoire?searchresult=1
@mucida Congratulations!
9/ These findings provide important insights into the mechanisms underlying the ability of the intestinal immune system to tolerate food antigens, and could have implications for the development of new therapies for food allergies.