Mapping the T cell repertoire to a complex gut bacterial community

Kazuki Nagashima, Aishan Zhao, Katayoon Atabakhsh, Minwoo Bae, Jamie E. Blum, Allison Weakley, Sunit Jain, Xiandong Meng, Alice G. Cheng, Min Wang, Steven Higginbottom, Alex Dimas, Pallavi Murugkar, Elizabeth S. Sattely, James J. Moon, Emily P. Balskus and Michael A. Fischbach ()
Additional contact information
Kazuki Nagashima: Stanford University
Aishan Zhao: Stanford University
Katayoon Atabakhsh: Stanford University
Minwoo Bae: Harvard University
Jamie E. Blum: Stanford University
Allison Weakley: Stanford University
Sunit Jain: Stanford University
Xiandong Meng: Stanford University
Alice G. Cheng: Stanford School of Medicine
Min Wang: Stanford University
Steven Higginbottom: Stanford University
Alex Dimas: Stanford University
Pallavi Murugkar: Stanford University
Elizabeth S. Sattely: Stanford University
James J. Moon: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Emily P. Balskus: Harvard University
Michael A. Fischbach: Stanford University

Nature, 2023, vol. 621, issue 7977, 162-170

Abstract: Abstract Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response1–5. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with complex defined communities (roughly 100 bacterial strains) and profile T cell responses to each strain. The pattern of responses suggests that many T cells in the gut repertoire recognize several bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all the bacteria-specific TCRs show a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that each recognize 18 Firmicutes. By screening three pooled bacterial genomic libraries, we discover that these 13 clonotypes share a single target: a conserved substrate-binding protein from an ATP-binding cassette transport system. Peripheral regulatory T cells and T helper 17 cells specific for an epitope from this protein are abundant in community-colonized and specific pathogen-free mice. Our work reveals that T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.

Date: 2023
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DOI: 10.1038/s41586-023-06431-8

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