# Impact of TCR-pMHC affinity on prostate-specific CD4+ T cell development and function

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2022 · $51,236

## Abstract

PROJECT SUMMARY/ABSTRACT
Foxp3+ CD4+ regulatory T (Treg) cells are critical for the prevention of autoimmunity and the regulation of
antitumor immunity, functioning in part by suppressing the activation and function of conventional T cells. Treg
cells depend on T cell receptor (TCR) stimulation for many facets of their biology, including thymic development,
peripheral differentiation, and suppressive function. In this regard, the affinity of TCR binding to self-peptides
complexed with MHC class II molecules (self-pMHCII) is thought to be a primary determinant of Treg cell
development and function. Existing models of thymic selection posit that intermediate TCR-pMHCII affinities –
at the threshold between positive and negative selection – promote optimal thymic Treg (tTreg) development,
allowing Treg cell clones to differentiate while also evading clonal deletion. In addition, it has been suggested
that Treg cells may be more sensitive to self-pMHC-II ligand than Foxp3neg conventional CD4+ T (Tconv) cells of
the same specificity, potentially contributing to Treg-mediated suppression in the periphery. However, these
proposed principles largely stem from the study of CD4+ T cells reactive to transgene-expressed foreign model
antigens. As the expression patterns, ligand densities, and TCR-pMHCII affinities of such engineered antigen
systems may not reflect those of endogenous self-antigens, it remains unclear whether the predictions of the
affinity model apply to Treg cell clones reactive to natural self-ligands. To address this question, we have
identified a panel of CD4+ T cell clones exhibiting varying sensitivities to the same endogenous tissue-restricted
antigen (TRA), Tcaf3646-658 (“C4” peptide). C4 is an unmodified I-Ab restricted prostatic self-peptide that drives
the thymic differentiation of a canonical Treg cell clone, MJ23. In other work, we also demonstrated that
monoclonal MJ23 Treg cells are highly enriched in oncogene-driven prostate tumors, indicating that the C4
peptide is a naturally occurring tumor-associated antigen. Our new data using C4/I-Ab tetramers demonstrate
that, in prostate-tumor-bearing mice, C4-reactive Treg and Tconv cells coexist in the tumor-draining lymph
nodes, yet only the former is detected within the tumor infiltrate. Whether TCR-pMHCII affinity contributes to
Tconv cell exclusion from prostate tumors remains unclear. Thus, this proposal seeks to define the role of TCR-
pMHCII affinity in the thymic and peripheral selection of CD4+ T cells reactive to the natural TRA and tumor-
associated antigen C4. The studies in Aim 1 will provide the first evidence testing the "TCR affinity" model for T
cell clones reactive to a natural self-peptide that directs tTreg cell differentiation, offering a unique opportunity to
validate and/or upend existing paradigms of thymic selection. The studies in Aim 2 mice will yield unique
mechanistic insights into the factors driving the peripheral selection of TRA-reactive Treg and Tco...

## Key facts

- **NIH application ID:** 10311518
- **Project number:** 5F30CA247264-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Donald Miguel Rodriguez
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,236
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311518

## Citation

> US National Institutes of Health, RePORTER application 10311518, Impact of TCR-pMHC affinity on prostate-specific CD4+ T cell development and function (5F30CA247264-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10311518. Licensed CC0.

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