# The Role of Microbial Antigen-Specific T Cells in Crohn's disease

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Microbial-antigen reactive T cells are the primary effectors of inflammatory damage in animal models of
Crohn's disease, causing T cell-mediated colitis only in the presence of gut microbiota. By focusing on a
proposed similar key role for T cells in Crohn's inflammation, we hypothesize that anti-flagellin antibodies that
are highly shared by Crohn's patients, and characterize an aberrant B cell response, are potential markers for
the presence T cell clonotypes that are reactive to the same gut commensal antigens (but different epitopes).
Of note, the presence of anti-CBir1 flagellin antibodies is the strongest predictor of severe, complicated
Crohn's disease.
 Our preliminary data demonstrate two features critical to the success of this long-term project. First,
there is a disease-specific repertoire of expanded T cells (defined by TCRβ CDR3 sequences) that is very
highly shared among Crohn's patients, making the study of these T cells' antigen reactivity relevant for the
majority of patients. Second, this highly shared T cell repertoire is associated with patterns of shared serum
anti-flagellin antibodies that are themselves restricted to Crohn's disease patients, suggesting a potential link
between aberrant B cell and T cell responses.
 To accomplish this study, we will enroll active Crohn's patients as well as remission Crohn's patients,
active ulcerative colitis patients and healthy controls to test for significant associations between profiles of
serum antibody reactivity to a panel of gut microbial antigens and the TCRβ CDR3 repertoire. The goal is to
identify high value CDR3 sequences that couple with cognate flagellin antigens. We plan to define the
distribution of these TCRβ CDR3 sequences among peripheral blood and gut tissue T cells subsets (effector,
regulatory and memory) with the goal of identifying sequences that segregate to a particular compartment or
phenotype and to see if the memory T cell subset is a reservoir of highly shared TCRβ CDR3 clonotypes.
Lastly we will measure which TCRβ CDR3 clonotypes are expanded in vitro following specific antigen
exposure to identify candidate antigen-specific sequences and test for their significant association with antigen
seropositivity and cell phenotype. These data will then be used to isolate single T cells from different
individuals who share identical expanded TCRβ CDR3 clonotypes in order to compare the similarity of
structure (α/β pairing), MHC specificity, and recognition of antigen. The focus will be on targeting highly
shared TCRβ CDR3 sequences that have been robustly linked with antigen-specific responses (cytokine
production, proliferation) and seropositivity across multiple Crohn's patients.
 The long-term goals of this project build on these data and aim to define the hierarchy of mechanisms
(antigen peptide binding motifs, MHC promiscuity, e.g.) that contribute to shared antigen reactivity among
Crohn's patients, to develop strategies that disrupt the antigen-specific T cel...

## Key facts

- **NIH application ID:** 9933824
- **Project number:** 5I01CX001530-03
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Peter Mannon
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933824

## Citation

> US National Institutes of Health, RePORTER application 9933824, The Role of Microbial Antigen-Specific T Cells in Crohn's disease (5I01CX001530-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933824. Licensed CC0.

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