A TCF1:GLUCOCORTICOID REGULATORY CIRCUIT CONTROLS IL-23-DRIVEN TH17 PATHOGENICITY - PROJECT SUMMARY CD4+ IL…

Assistance award details

Assistance award identifier

ASST_NON_R01AI176341_075

FAIN

R01AI176341

Recipient

BRIGHAM & WOMENS HOSPITAL INC

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$2,055,024

Period

Feb 1, 2023 – Jan 31, 2028

Fiscal year

2023

Place of performance state

MA

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

A TCF1:GLUCOCORTICOID REGULATORY CIRCUIT CONTROLS IL-23-DRIVEN TH17 PATHOGENICITY - PROJECT SUMMARY CD4+ IL-17-PRODUCING T HELPER CELLS (TH17) ARE KNOWN DRIVERS OF CENTRAL NERVOUS SYSTEM (CNS) AUTOIMMUNE INFLAMMATION IN MULTIPLE SCLEROSIS (MS), YET NOT ALL TH17 CELLS DRIVE DISEASE. INDEED, TWO MAJOR TH17 SUBTYPES HAVE BEEN DESCRIBED IN BOTH MICE AND HUMANS: HOMEOSTATIC OR NON-PATHOGENIC (NPTH17) THAT MAINTAIN THE STEADY STATE IN TISSUE AND INFLAMMATORY OR PATHOGENIC TH17 (PTH17) THAT DRIVE DESTRUCTIVE TISSUE INFLAMMATION. IMPORTANTLY, NPTH17 ARE PRECURSORS OF PTH17 AND IL-23 IS KNOWN TO BE THE SWITCH FACTOR FOR CONVERSION OF NPTH17 TO PTH17. HOWEVER, THE MECHANISMS BY WHICH IL-23 DRIVES THIS CONVERSION ARE NOT WELL UNDERSTOOD. IDENTIFYING THESE MECHANISMS WILL PROVIDE CRITICAL INSIGHT FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTIONS FOR MS. GENETIC VARIANTS IN TCF7, THE GENE ENCODING THE TRANSCRIPTION FACTOR TCF-1, HAVE BEEN ASSOCIATED WITH DISEASE SUSCEPTIBILITY IN MS IN GENOME-WIDE ASSOCIATION STUDIES, BUT THE UNDERLYING MECHANISMS REMAIN UNKNOWN. NOTABLY, TCF-1 HAS BEEN IMPLICATED IN TH17 BIOLOGY, BUT ITS ROLE REMAINS UNCLEAR DUE TO CONFLICTING DATA GENERATED IN MODELS THAT HAVE EITHER DEFECTIVE T CELL DEVELOPMENT OR THAT STUDY TCF-1 INDIRECTLY. USING MICE THAT CONDITIONALLY DELETE TCF7 ONLY IN MATURE T CELLS, AND THUS HAVE NORMAL T CELL DEVELOPMENT, WE HAVE FOUND THAT TCF-1-DEFICIENT TH17 CELLS MAY NOT REQUIRE IL-23R SIGNALING FOR ACQUIRING PATHOGENIC POTENTIAL. INDEED, WE HAVE FOUND THAT TCF-1 IS DIFFERENTIALLY REGULATED IN NPTH17 AND PTH17 IN VIVO AND THAT IL-23 SHUTS DOWN TCF-1 EXPRESSION. OUR PRELIMINARY DATA FURTHER UNCOVER A PUTATIVE REGULATORY CIRCUIT THAT LINKS IL-23, TCF-1, AND ENDOGENOUS GLUCOCORTICOID (GC) SIGNALING. WE HAVE FOUND THAT NPTH17 ARE STEROIDOGENIC. THEY CAN PRODUCE GCS, WHICH IN TURN, SUSTAIN TCF-1 EXPRESSION, OPPOSE IL23R SIGNALING, AND RESTRAIN TH17 PATHOGENICITY. IN CONTRAST, IL-23 SHUTS DOWN STEROIDOGENESIS IN NPTH17 CELLS. ACCO