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Unraveling shared and unique mechanisms of autoimmunity using systems immunology approaches: Regulatory T cell dysfunction in Lupus

Award Number: K08AR086316
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Unraveling shared and unique mechanisms of autoimmunity using systems immunology approaches: Regulatory T cell dysfunction in Lupus - Autoimmune diseases share many genetic risk factors, manifestations and treatment responses, yet are often studied in individual research silos without consideration of their rich overlapping pathophysiology. By studying these diseases in combination, we create a multifaceted evaluation that 1) enhances the shared mechanisms uniting these diseases, and 2) highlights the unique factors that mechanistically distinguish one disease from another. The studies within this proposal use systems immunology approaches to demonstrate commonalities and distinctions in peripheral T cells at a cellular and transcriptional level in autoimmunity (Aim 1). Dr. Nestor has already created a large integrated dataset of 3.5 million cells across 11 autoimmune conditions for use in these studies, which is notable for 10 distinct regulatory T (Treg) cell populations, 2 of which are markedly upregulated in lupus. Lupus is a complex heterogeneous autoimmune disease that can have devastating consequences yet still only has limited treatment options. To validate the above findings, a prospective cohort of patients from the Lupus Biobank that Dr. Nestor created, will be characterized using multiomics techniques with a focus on isolating the Tregs of interest and defining their functionality (Aim 1). To further investigate the role of Tregs in the pathophysiology of lupus and determine their potential as therapeutic targets, a novel interleukin-2 (IL-2) mutein will be assessed in the MRL/lpr mouse model of lupus for its ability to induce Treg expansion and ameliorate disease (Aim 2). Low-dose IL-2 has yielded positive results in lupus previously, but the IL-2 mutein proposed for use in these experiments has an extended half-life and increased specificity allowing for less frequent dosing and minimizing off-target side effects. The studies proposed above illustrate a well-defined research pathway that leverages a large cross-autoimmunity dataset to identify shared and disease-specific perturbations in T cells and the downstream validation of these findings in both patients and a mouse model of lupus. The enclosed proposal entails a rigorous career development plan and robust research proposal that will ensure Dr. Jacquelyn Nestor’s success over the five-year funding period and beyond. Dr. Nestor is an Associate Physician at Massachusetts General Hospital (MGH) and Instructor in Medicine at Harvard Medical School (HMS). Under the guidance of her mentors, Drs. Andrew Luster and Alexandra-Chloé Villani, and within the greater MGH, HMS and Broad Institute immunology research communities, she will have access to the necessary mentorship, scientific expertise, and technology required to complete her proposed studies. Her proposal will build skills in single-cell sequencing, computational analysis, and Treg identification and functional evaluation. This expertise, in combination with her already outstanding research background in lupus, will support her ultimate R01 proposal and successful transition to independence as a productive physician scientist with a basic-translational research program utilizing systems immunology approaches in lupus.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $165,240 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/20/2026	NEW	$165,240
														Subtotal = $165,240

Grand Total All Awards = $165,240

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Unraveling shared and unique mechanisms of autoimmunity using systems immunology approaches: Regulatory T cell dysfunction in Lupus

Award Number: K08AR086316

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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