Regulatory t cell dysfunction as a biomarker for personalized therapeutic target identification in SLE

The National Institute of Allergy and Infectious Diseases awarded Weill Medical College of Cornell University $647,571 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate regulatory T cell dysfunction as a biomarker for personalized therapeutic targeting in systemic lupus erythematosus.

The research uses single-cell transcriptomics to characterize two transcriptionally distinct patient subgroups based on naive regulatory T cell (nTreg) phenotype. In one subgroup, nTregs exhibit profound transcriptional divergence, FOXP3 instability, and loss of suppressive function upon restimulation, with this phenotype correlating with increased disease activity and renal involvement including lupus nephritis. The project aims to stratify SLE patients by nTreg phenotype, assess correlations between dysfunctional nTregs and disease activity or organ damage, and determine whether these cells predict disease flares or end-organ damage through longitudinal analysis. The work will identify selective surface markers enabling tracking of these cells in blood and tissues to support biomarker discovery and targeted therapeutic strategies. Additional objectives include defining the effector functions of dysfunctional nTregs and their influence on B-cell and myeloid-cell responses, and dissecting molecular pathways driving FOXP3 destabilization through CRISPR-based functional screens, epigenetic and metabolic profiling, and investigation of proinflammatory cytokine and microbiota-derived signals.

Work is performed at Weill Medical College's location in New York, New York. The period of performance extends from September 1, 2026, through August 31, 2027.

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation, autoantibody production, and multiorgan inflammation. Our research aims to elucidate the role of regulatory t cells (tregs) in SLE to improve patient stratification and identify novel therapeutic targets. Using single-cell transcriptomics, we identified two transcriptionally distinct subgroups of SLE patients. In the G1 subgroup, naïve tregs (ntregs) resemble those of healthy donors, whereas in the G2 subgroup, ntregs exhibit profound transcriptional divergence, FOXP3 instability, and loss of suppressive function upon restimulation. The presence of G2 ntregs correlates with increased disease activity (DA) and renal involvement, including lupus nephritis (LN). Upon restimulation, G2 ntregs (r-G2 ntregs) transition into "EX-tregs"-like cells with TH2/TFH-like and cytotoxic features, potentially promoting b-cell activation and expansion of pathogenic DN2 b cells. Aim 1 will stratify SLE patients based on their G1 or G2 ntreg phenotype and assess correlations between G2 ntregs, DA, and organ damage. Through longitudinal analysis, we will determine whether G2 ntregs predict disease flares or the development of end-organ damage. We will also identify selective surface markers that enable tracking of these cells in blood and tissues, laying the groundwork for biomarker discovery and targeted therapeutic strategies. Aim 2 will define the effector functions of r-G2 ntregs and evaluate how they influence b-cell and myeloid-cell responses. Aim 3 will dissect the molecular pathways driving FOXP3 destabilization in r-G2 ntregs by integrating crispr-based functional screens with epigenetic and metabolic profiling and by investigating the contribution of proinflammatory cytokines and microbiota-derived signals. Together, these studies will elucidate how treg instability contributes to systemic immune dysregulation in SLE, identify biomarkers predictive of disease flares and organ damage, and uncover therapeutic strategies aimed at restoring treg stability and immune tolerance.