Sle1 was initially identified as the locus with the highest linkage to lupus nephritis in the NZM2410 model. The characterization of the B6.Sle1 congenic mice showed that Sle1 controls the loss of tolerance to chromatin and that it is functionally expressed in B and CD4+ T cells. Sle1 expression is required for disease to develop, and its suppression by Sles1/Sle4 abrogates disease regardless of the presence of other susceptibility loci. Because Sle1 is responsible for a defining trigger in lupus pathogenesis, the loss of tolerance to nuclear antigens, and because mouse models expressing Sle1 are extensively used, the identification of the Sle1 genes and the elucidation of the mechanisms they control will greatly advance our understanding of lupus pathogenesis. Starting from a region over 40 Mb long, we have identified five loci, Sle1a1 and Sle1a2, Sle1b, and Sle1c1 and Sle1c2. In this project, we propose to characterize how two genes, Pbx1, corresponding to Sle1a1, and Esrrg, corresponding to Sle1c2, control the plasticity and stability of CD4+ T cells. The functions of Pbx1 and Esrrg are well known in multiple tissues, but not in the immune system. Lupus-associated Pbx1-d is a dominant-negative allele, while Esrrg is expressed at lower levels in Sle1c2 T cells. We have published results as well as strong preliminary data supporting the scientific premise that the Pbx1 and Esrrg lupus alleles promote instability or dysfunction in Foxp3+ regulatory CD4+ T cells (Treg), and promote the expansion of follicular helper T cells (Tfhs), two common features of lupus in mice and in humans. Ample evidence exists that Treg cells are unstable in inflammatory conditions, as they can lose Foxp3 expression and their suppressive capacity, while acquiring pro-inflammatory functions. Besides the presence of inflammatory cytokines, the mechanisms governing this process are poorly defined. We have also evidence that Pbx1 and Esrrg control the expansion of the follicular regulatory T cell (Tfr) pool. This relatively newly described T cell subset regulates germinal center function. The frequency of Tfrs is reduced in SLE patients in correlation with disease activity. Tfrs differentiate from Tregs, but the factors that regulate their differentiation and their relative frequency relative to Tfh are largely unknown. We propose that Pbx1 and Esrrg are two novel factors directly controlling Treg stability, and directly or indirectly Tfr and Tfh expansion by two different mechanisms. Our preliminary results suggest that chromatin pioneer transcription factor (TF) Pbx1 regulates the expression of metabolic genes and controls access to the Treg CNS2 locus controlling the stability of Foxp3 expression, while Esrrg controls Treg survival and quiescence through mitochondrial metabolism, which has been shown to regulate Foxp3 expression. We have assembled the tools to test this hypothesis, first using novel mouse strains to dissect the consequences of Pbx1 or Esrrg deficiency in CD4+ T cells and Tregs (Specific Aims 1 and 2), then in human T cells (Specific Aim 3). This project provides for the first time the opportunity to characterize how two genes linked to autoimmune phenotypes regulate CD4+ T cell plasticity.

Public Health Relevance

Systemic lupus erythematosus is a disease with a complex genetic susceptibility in which only a few susceptibility genes have been characterized relative to disease development. We have identified two mouse lupus susceptibility genes that regulate the functions of T lymphocytes. This project is designed to characterize the function of these two genes to better understand the processes that regulate lupus development.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Johnson, David R
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University of Florida
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Choi, Seung-Chul; Titov, Anton A; Abboud, Georges et al. (2018) Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells. Nat Commun 9:4369
Choi, Seung-Chul; Xu, Zhiwei; Li, Wei et al. (2018) Relative Contributions of B Cells and Dendritic Cells from Lupus-Prone Mice to CD4+ T Cell Polarization. J Immunol 200:3087-3099
Li, Wei; Titov, Anton A; Morel, Laurence (2017) An update on lupus animal models. Curr Opin Rheumatol 29:434-441
Niu, Yuxin; Sengupta, Mayami; Titov, Anton A et al. (2017) The PBX1 lupus susceptibility gene regulates CD44 expression. Mol Immunol 85:148-154
Yin, Yiming; Choi, Seung-Chul; Xu, Zhiwei et al. (2016) Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus. J Immunol 196:80-90
Li, Wei; Sivakumar, Ramya; Titov, Anton A et al. (2016) Metabolic Factors that Contribute to Lupus Pathogenesis. Crit Rev Immunol 36:75-98
Choi, Seung-Chul; Hutchinson, Tarun E; Titov, Anton A et al. (2016) The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation. J Immunol 197:458-69
Lu, Shun; Zeumer, Leilani; Sorensen, Heather et al. (2015) The murine Pbx1-d lupus susceptibility allele accelerates mesenchymal stem cell differentiation and impairs their immunosuppressive function. J Immunol 194:43-55
Xu, Zhiwei; Morel, Laurence (2015) Contribution of B-1a cells to systemic lupus erythematosus in the NZM2410 mouse model. Ann N Y Acad Sci 1362:215-23
Yin, Yiming; Choi, Seung-Chul; Xu, Zhiwei et al. (2015) Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med 7:274ra18

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