# Self-Peptides Bound to MHC Class II in T Cell Selection

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $595,054

## Abstract

Project Summary
X-linked transcription factor (TF) Foxp3 is a lineage specification factor for regulatory T (Treg) cells lineage,
which is vital for limiting autoimmunity and inflammation. Foxp3 loss-of-function causes fatal human autoimmune
IPEX syndrome and similarly deadly disease in mice. Increasing realization that Treg cells are playing an
important role in diverse physiological and pathological processes, including autoimmunity, allergy, tissue repair,
transplantation, metabolic inflammation, and degenerative disease, forms the basis for their potential use as
cellular therapeutics. Foxp3 expression is essential for Treg cell differentiation and its continuous expression in
differentiated Treg cells is required for their suppressor function. Thus, Foxp3-dependent transcriptional program
lies at the core Treg cell biology. However, in-depth understanding of the Foxp3-mediated gene expression
program and preceding events during Treg cell differentiation required for its execution is lacking. Our long-term
goal in this application is to generate essential new knowledge of fundamental mechanistic underpinning of Treg
biology – its transcriptional control by Foxp3. Based on our recent studies, we will test a hypothesis that
developmental history “prepares” specific sets of chromatin sites in precursor cells for Foxp3 binding through
activity of “companion” TF preceding and subsequent to Foxp3 expression. This RO1 renewal application aims
to identify key TFs guiding Treg differentiation and facilitating proper direct and indirect Foxp3-dependent control
of gene expression defining Treg cell identity and function. In this proposal, we will leverage extensive natural
genetic variation in laboratory C57Bl/6 (B6) and wild-derived CAST/EiJ (Cast) and SPRET/EiJ (Spret) mice,
which represent different taxa separated over 1 million years ago, and take advantage of novel unique genetic
tools recently generated in the lab to address major mechanistic questions in Treg cell biology. In Aim 1, we will
investigate direct and indirect transcriptional regulation of gene expression by Foxp3 using natural genetic
variation. In Aim 2, we will explore dynamics of regulation of gene expression by Foxp3 by studying temporal
establishment of Foxp3-mediated transcriptional program. In Aim 3, we will identify stable and reversible
components of Foxp3-dependent transcriptional program directly and indirectly controlled by Foxp3 and, thereby,
reveal core Foxp3-dependent functional program in Treg cells. These studies will elucidate fundamental
mechanisms of Foxp3-dependent regulation of gene expression in an unbiased and genetically controlled
manner by leveraging power of genetics of evolutionary distant mice, high throughput genomics, and cutting-
edge computational approaches combined with genome editing and biochemical and immunological analyses.

## Key facts

- **NIH application ID:** 10468044
- **Project number:** 5R01AI034206-29
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alexander Y Rudensky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $595,054
- **Award type:** 5
- **Project period:** 1992-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468044

## Citation

> US National Institutes of Health, RePORTER application 10468044, Self-Peptides Bound to MHC Class II in T Cell Selection (5R01AI034206-29). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10468044. Licensed CC0.

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