# The role of Runx1 in the regulation of T cell anergy

> **NIH NIH F31** · MAYO CLINIC ROCHESTER · 2021 · $25,739

## Abstract

Abstract: T cell anergy is a programmed state of cellular hyporesponsiveness that prevents the propagation of
an immune response to self. Thus, anergy is a critical component of self-tolerance. Consequently, the
development and maintenance of the anergy program in T cells is tightly controlled by many mechanisms, both
cell-intrinsic and cell-extrinsic. Since anergy is important in self-tolerance, it is critical to understand the
complex biology that regulates the initiation and regulation of the anergy program. We have found in wild-type
(WT) mice that lower expression of the transcription factor Runx1 is associated with anergic T cells, defined by
co-expression of the cell-surface markers CD73 and FR4. Furthermore, conditional deletion of Runx1 in T cells
using a CD4-Cre produces a higher frequency of T cells that co-express CD73 and FR4. This supports the
hypothesis that Runx1 suppresses the development of anergy in CD4+ T cells. CD4-Cre Runx1 cKO mice have
a block in T cell maturation and have very few CD4+ T cells in peripheral lymphoid organs. To bypass this
maturation defect, and test the role of Runx1 in peripheral CD4+ T cells, we have generated a novel 1:1 mixed
bone marrow chimera (BMC) system using Estrogen Receptor (ER)-Cre Runx1 cKO bone marrow mixed with
B6.SJL Wild Type (WT) bone marrow. This bypasses the maturation defect by deleting Runx1 in peripheral
CD4+ T cells in a tamoxifen inducible manner after they have completed maturation. Furthermore, half the
cells are Runx1-sufficient allowing for analysis of T cell-intrinsic effects. In this system, we have found that
Runx1 regulates the cell-intrinsic induction of anergy, as increased frequency of co-expression of CD73 and
FR4 in peripheral CD4+ T cells is only seen in the ER-Cre Runx1 cKO cells and not the B6.SJL WT cells
derived from the same mouse. Aim 1 of the proposed studies will determine critical gene targets Runx1
regulates to control CD4+ T cell anergy. To do this, candidate genes identified by RNA-sequencing will be
analyzed in our novel ER-Cre system, and their role in anergy will functionally assessed. Surprisingly, both the
ER-Cre Runx1 cKO and the B6.SJL CD4+ T cells in the tamoxifen treated animals fail to proliferate upon in
vitro TCR stimulus, suggesting that Runx1 regulates a cell-extrinsic signaling mechanism controlling tolerance.
Aim 2 will define key mechanisms anergic Runx1-deficient CD4+ T cells use to tolerize wild type CD4+ T cells.
To complete this aim we will examine the role of candidate genes in wild type cells. Further investigation of the
role of Runx1 in CD4+ T cell anergy will provide insight into how the immune system initiates and maintains
self-tolerance.

## Key facts

- **NIH application ID:** 10311471
- **Project number:** 5F31AI147438-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Drew N Wilfahrt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $25,739
- **Award type:** 5
- **Project period:** 2020-09-30 → 2022-01-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311471

## Citation

> US National Institutes of Health, RePORTER application 10311471, The role of Runx1 in the regulation of T cell anergy (5F31AI147438-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10311471. Licensed CC0.

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