# Biochemical and cellular analysis of regulatory T cells reactive to a natural self antigen

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $650,415

## Abstract

PROJECT ABSTRACT
Foxp3+ regulatory T (Treg) cells are critical for the regulation of immune responses to self, foreign, and tumor-
associated antigens, prompting considerable interest in the therapeutic manipulation of Treg cells in the
context of cancer, autoimmunity, and transplantation. Over the past decade, a paradigm has emerged holding
that thymic-derived Treg (tTreg) cells recognize self antigens. Furthermore, substantial evidence indicates that
antigen recognition is critical for many aspects of Treg biology, including development, activation, anatomical
distribution, and suppressor function. However, the natural self antigens recognized by tTreg cells remained
unidentified. Without this knowledge, it was not possible to determine the biochemical nature of antigen
recognition by Treg cells, to elucidate the role of TCR signal strength in promoting Treg development and
clonal deletion, and to directly characterize endogenous antigen-specific Treg populations using peptide/MHC
multimers. In recent work, we have identified a self antigen recognized by an endogenous population of
naturally occurring Treg cells. The antigen, referred to as “C4” in this proposal, is an unmodified I-Ab-restricted
peptide derived from a prostate-specific protein, and is recognized by a canonical Treg clone named “MJ23”.
The studies outlined in this proposal will utilize the MJ23 TCR:C4/I-Ab system to address long-standing critical
gaps in knowledge regarding Treg biology and the mechanisms by which dominant and recessive tolerance
are enforced. The objectives of this proposal are to elucidate the biochemical nature of pMHC recognition by
tTreg TCRs, to identify the mechanisms driving the thymic development of C4-specific Treg cells, and to
elucidate the processes coordinating the peripheral homeostasis of C4-specific Tregs. It is our central
hypothesis that high-affinity recognition of C4/I-Ab drives the thymic development of C4-specific Treg cells and
the further selection of optimal C4-specific Treg clones in the periphery. We will test our central hypothesis
and accomplish the objectives of this application by pursuing the following specific aims. In Aim 1, we will
elucidate the molecular basis of Treg TCR recognition of self pMHC. In Aim 2, we will identify the signals
driving the thymic development of C4-specific Treg cells. In Aim 3, we will determine the impact of peripheral
selection on C4-specific Treg cells. The work outlined in this proposal is expected to reveal the biochemical
nature of self antigen recognition by naturally occurring tTreg specificities. Moreover, the studies are expected
to elucidate whether TCR signal strength is a primary determinant of whether self-reactive thymocytes will
differentiate into the Treg lineage or undergo clonal deletion. Finally, these studies are expected to reveal the
extent to which antigen encounter in the periphery shapes the repertoire of antigen-specific tTreg cells
throughout life. In all, our work is expec...

## Key facts

- **NIH application ID:** 9938408
- **Project number:** 5R01AI126756-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Erin June Adams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,415
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938408

## Citation

> US National Institutes of Health, RePORTER application 9938408, Biochemical and cellular analysis of regulatory T cells reactive to a natural self antigen (5R01AI126756-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938408. Licensed CC0.

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