Wednesday, February 5, 2025 2/5/2025

T peripheral regulatory cells as modulators of T cell-B cell interactions in arthritis

Award Number: R01AR083424
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

PROJECT SUMMARY/ABSTRACT T cell-B cell interactions that result in B cell maturation and antibody production were once thought to occur exclusively in lymphoid organs. It is now appreciated that T peripheral helper (Tph) cells provide excessive help to B cells resulting in autoantibody production in inflamed peripheral tissues. Such disordered Tph cell-B cell responses have been implicated in some forms of chronic inflammatory arthritis in both adults and children. The pathways that regulate the Tph cell-B cell axis in non-lymphoid tissues are not understood. By studying joint fluid from patients with juvenile idiopathic arthritis (JIA), we found evidence of dysregulated Tph cell-B cell responses in children with early-onset and anti-nuclear antibody (ANA) positive forms of the disease. Our preliminary studies also identified a novel T cell subset, T peripheral regulatory (Tpr) cells, in the joints of patients with JIA. These Tpr cells co-express regulatory T (Treg) and B cell-helper T cell factors. Further, Tpr cells have the ability to inhibit Tph cell-B cell interactions that result in plasmablast generation in our T cell-B cell co-culture system. The central hypothesis of this application is that Tpr cells restrain Tph cell-B cell interactions in the joints of patients with inflammatory arthritis. The central hypothesis in this research proposal will be tested with two Specific Aims that will be conducted with biosamples (peripheral blood, synovial fluid, tonsil tissue) from children with JIA as well as healthy controls. Through our established T cell-B cell co-culture system, Aim1 will assess the mechanisms by which Tpr cells regulate Tph cell-B cell interactions. We will test the hypothesis that Tpr cells are uniquely equipped to inhibit proliferation and cytokine production in B cell-helper T cells as well as antibody production, class switching, and maturation in B cells by inducing alterations in gene expression and metabolism. Using a multiomics approach coupled with functional assays, Aim 2 will define the developmental pathways and transcriptional program required for Tpr functionality. We will test the hypothesis that Tpr cells differentiate from Treg cells in the joint and have a unique transcriptional program that is distinct from other Treg subsets and ensures Tpr functionality in tissues. The research is innovative because we will use a systems immunology approach coupled with synovial fluid samples from children with JIA to study T cell-B cell responses directly from affected tissues. Completion of this research will be significant because Tpr cells represent a novel regulatory pathway with the capacity to restrain Tph cell-B cell responses and ameliorate tissue-specific inflammation in arthritis and other autoimmune diseases.


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: 2025 ( Subtotal = $463,780 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/11/2024	NON-COMPETING CONTINUATION	$463,780
														Subtotal = $463,780

Issue Date FY: 2024 ( Subtotal = $492,123 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/14/2023	NEW	$492,123
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	1/10/2024	NEW	$0
														Subtotal = $492,123

Grand Total All Awards = $955,903

Top

All Categories

About

Search

Reports

Data Submission

Award Information

T peripheral regulatory cells as modulators of T cell-B cell interactions in arthritis

Award Number: R01AR083424

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer