# Development, stability, and antigen specificity of T follicular regulatory phenotype cells

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
 Many human autoimmune diseases are associated with the expansion of self-reactive B cells and
subsequent autoantibodies targeting self-constituents. Even in healthy individuals, an appreciable fraction of
self-reactive B cells exists, implying the existence of extrinsic layers that restrain overt humoral autoimmunity.
Foxp3+ T follicular regulatory (Tfr) cells—defined in part by their localization within the B cell follicle and the
germinal center (GC)—are one such layer. Selective removal of Tfr cells in mice at the peak of an immune
response results in a substantial increase of autoreactive antibodies, while low Tfr cell frequencies are negatively
associated with human autoimmune diseases, further suggesting a key role in the regulation of B cell tolerance.
Most previous work has studied Tfr cells at the peak of a GC reaction, meaning that their contributions at steady
state and following cessation of a GC are unknown. Without knowledge of the entire life cycle of Tfr cells—
including their initial development, phenotype differentiation, and maintenance outside of a GC—we will remain
ignorant to additional roles that these cells likely play in maintaining immunity. Early adoptive transfer studies
have suggested that the majority of Tfr cells derive from existing regulatory T cell (Treg) precursors. Alternatively,
some lines of evidence controversially hint that a small subset of Tfr cells may also differentiate from Foxp3neg T
helper cells of foreign antigen specificity, though such populations have not been consistently identifiable. Based
on these data, we hypothesize that most Tfr-phenotype cells elicited during a GC reaction represent stable pre-
existing thymus-derived Treg cells reactive to self-antigens. As proposed below, we will define the development,
differentiation, and stability of Tfr cells. We will also assess the extent to which Tfr cells are reactive to foreign
versus self-antigens. To accomplish these aims, we will generate T cell receptor retrogenic mice expressing
monoclonal populations of Tfr biased clones of interest, allowing us to study naturally occurring Tfr cells at the
clonal level. We will track the entire in vivo life cycle of individual Tfr biased clones, both at steady state and after
cessation of a GC response, providing key insights into the biology of these cells. Finally, we will investigate the
antigen specificity of Tfr cells by assessing their in vitro reactivity to dendritic cells or B cells loaded with self or
foreign antigens. The findings obtained from this project will provide us with a clear model of the complete
developmental trajectory and potential foreign reactivity of Tfr cells. This model will enable us to further study
these cells in previously unappreciated contexts, thereby improving our understanding of how Tfr cells may
succeed—or fail—to prevent autoimmunity.

## Key facts

- **NIH application ID:** 10996447
- **Project number:** 1F31AI186394-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Taylor Graham
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-11-01 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996447

## Citation

> US National Institutes of Health, RePORTER application 10996447, Development, stability, and antigen specificity of T follicular regulatory phenotype cells (1F31AI186394-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10996447. Licensed CC0.

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