# Regulation of central tolerance and Treg development by recirculating Treg

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $387,500

## Abstract

PROJECT SUMMARY
Effective cell-based immunity depends on two major systems: (i) the ability to generate a diverse TCR
repertoire capable of recognizing antigens from previously unencountered pathogens, and (ii) the ability to
discriminate between self- and non-self-antigens and prevent autoimmunity. Inappropriate balance between
these two systems causes a variety of disease states including ineffective tumor immune surveillance and poor
pathogen clearance due to gaps in the TCR repertoire, or the onset of autoimmunity and off target
immunopathology during infection. Autoimmunity can be curtailed by deleting autoreactive TCRs or diverting
them into the Treg lineage in the thymus. However, given the high degree of cross-reactivity of TCRs this
process cannot be truly efficient at removing all self-reactive TCRs as this would remove much of the potential
diversity of the conventional TCR repertoire, thereby impairing immunity to pathogens. Thus, a key biological
question is how thymic selection functions to balance protection against autoimmunity while providing
effective immunity against pathogens. We hypothesize that a unique population of thymic recirculating
Treg cells (RT-Treg) act as a rheostat to decrease the stringency of selection once peripheral Treg cell
tolerance is established, thereby allowing for a more diverse and pathogen-reactive conventional
immune system. This will be examined in two specific aims: Aim 1: Define RT-Treg heterogeneity and
functional consequences of RT-Treg accumulation. Aim 2: Identify the mechanisms by which RT-Treg cells affect
immune repertoires and mTEC numbers. The proposed experiments will elucidate the role that RT-Treg play in
governing the stringency of central tolerance, both promoting effector cell diversity and ensuring maintenance
of self-tolerance by Treg cells.

## Key facts

- **NIH application ID:** 10833484
- **Project number:** 5R01AI159554-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael Archibald Farrar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833484

## Citation

> US National Institutes of Health, RePORTER application 10833484, Regulation of central tolerance and Treg development by recirculating Treg (5R01AI159554-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10833484. Licensed CC0.

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