# Characterization of SLE-susceptibility loci on mouse chromosome 1

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $703,044

## Abstract

Project summary
Sle1, the strongest lupus susceptibility locus in the NZM2410 mouse model, is responsible for the loss of
tolerance to chromatin, including the production of autoreactive CD4+ T cells. It corresponds to a cluster of loci,
including Sle1a1 that enhances effector CD4+ T cell function and reduces the number and function of peripheral
(p)Treg cells. Sle1a1 corresponds to the expression of Pbx1-d, a splice isoform of the transcription factor Pbx1
that lacks the DNA- and Hox-binding domains, as compared to Pbx1-b, the common isoform in lymphocytes.
Pbx1-d is expressed at a higher level in CD4+ T cells from B6.Sle1a1 and NZM2410 mice, and from SLE patients,
as compared to B6 mice and healthy controls (HC). Importantly, the PBX1 isoforms and the protein sequence
are identical between mice and humans. In the previous cycle of funding, we showed that either Pbx1-d Tg
expression in T cells or the FOXP3-specific deletion of Pbx1 impaired the maintenance of pTregs, resulting in a
global CD4+ T cell activation, which increased atherogenic lesions as well as autoimmunity in dyslipidemic mice.
Our work therefore established a novel role for Pbx1 to maintain Treg homeostasis. We also showed that Pbx1
expression in CD4+ T cells is the highest in Tregs, and that Pbx1-d is a dysfunctional protein through multiple
mechanisms. Our work is the first to associate a specific genetic variation to the well-documented alterations in
Tregs in human and mouse lupus. A SNP decreasing PBX1 expression in B cells has also been recently
associated to SLE susceptibility and a B-cell specific deletion of Pbx1 enhanced B cell responses in mice.
Therefore, Pbx1 represents a unique lupus susceptibility gene in both mice and humans that impairs Tregs
through the over-expression of Pbx1-d and B cells through a reduced global expression. In this competitive
renewal, we propose to characterize the mechanisms by which Pbx1 regulates pTreg maintenance and function
at the molecular and cellular levels, and how this process is altered by the expression of lupus-susceptibility
allele Pbx1-d. In addition, we propose to characterize the combined effects of a reduced Pbx1 expression in B
cells and overexpression of Pbx1-d in Tregs to comprehensively define the contribution of Pbx1 to lupus
susceptibility. To achieve these goals, we propose three specific aims conducted in mice as well as in PBMCs
obtained from SLE patients and HCs. Aim 1. To characterize the functional consequences of Pbx1-d expression
in Tregs using cellular assays with murine cells that express only Pbx1-b or Pbx1-d, and human cells based on
their PBX1-D expression. Aim 2. To define the molecular pathways regulated by Pbx1 and Pbx1-d in Tregs with
gene expression profiling, Pbx1 binding sites and chromatin accessibility, scRNA-Seq, and proteomics. Aim 3.
To define the consequences of Pbx1-deficiency or Pbx1-d expression in Tregs combined with Pbx1 deficiency
in B cells. The proposed experiments will provide for t...

## Key facts

- **NIH application ID:** 10979769
- **Project number:** 2R01AI045050-24
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Laurence Morel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $703,044
- **Award type:** 2
- **Project period:** 1999-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979769

## Citation

> US National Institutes of Health, RePORTER application 10979769, Characterization of SLE-susceptibility loci on mouse chromosome 1 (2R01AI045050-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979769. Licensed CC0.

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