Impact of transcriptional regulators in peripheral T helper cells (Tph) in lupus
The hallmarks of systemic lupus erythematosus include immune T cells and B cells that inappropriately attack one’s own cells, autoantibodies, and inflammatory substances called type 1 interferons. A group of T cells called T peripheral helper (Tph) cells is thought to misdirect immune response seen in lupus by producing an inflammatory substance CXCL13 that attaches to a molecule CXCR5 on the surface of B cells which may lead to the generation of autoantibodies that attack and damage organs in patients with lupus.
Dr. Vanessa Wacleche will use innovative technologies to study how Tph cells control the production of CXCL13. Dr. Wacleche will also study if interferon-alpha, which is the main type 1 interferon causing inflammation in lupus, is responsible for Tph cells maturation and expansion as well as production of CXCL13 by these cells.
What this study means for people with lupus:
The findings will generate new strategies to control CXCL13 production by Tph cells that could eventually lead to the development of novel treatments for lupus patients.
Immunological hallmarks of SLE include activation of autoreactive T cells and B cells, generation of autoantibodies, and production of inflammatory cytokines, including high secretion of IFN-??, leading to end-organ damage. The T cell populations that help B cells in autoimmune diseases vary in phenotype and include T follicular helper (Tfh) cells, which reside in follicles of secondary lymphoid organs, as well as T peripheral helper (Tph) cells, which are B cell-helper T cells that migrate to inflamed peripheral tissues such as the rheumatoid joint and the kidney. Tph cells were initially discovered in the context of rheumatoid arthritis and have been reported to be expanded in SLE patients. Expansion of Tph cells represents an important abnormality among circulating CD4+ T cells in disease pathogenesis. Tph cells and Tfh cells share the ability to recruit B cells via the production of a B cell chemoattractant CXCL13 and then promote B cell differentiation through both surface interactions and secreted cytokines. The signals that regulate development and function of Tph cells and Tfh cells in autoimmunity remain incompletely described, and particularly little is known about T cell production of CXCL13. We hypothesized that Tph cells are critical drivers of pathologic T cell-B cell interactions and represent a promising therapeutic target in SLE. Interfering with Tph cell function would abrogate CXCL13 production and the accumulation of lymphoid aggregates within chronically inflamed tissues.
The proposed research project mainly focuses on identifying extrinsic signals and intracellular regulators involved in CXCL13 regulation in Tph cells. In the current project of the applicant, Dr. Vanessa Sue Wacleche, the transcription factor aryl hydrocarbon receptor (AHR) was discovered as a negative regulator of CXCL13 in SLE. These findings are part of a manuscript in progress. The proposed research project explores the role of IFN-?? in the expansion of Tph cells producing CXCL13. Preliminary results indicate that IFN-?? increases CXCL13 production, independently of AHR signaling. The objectives of this proposed plan are 1) to determine the ability of IFN-?? to promote Tph cell differentiation and 2) to identify transcriptional regulators of IFN-??-induced CXCL13 production. This project aims to connect two critical features of SLE: the overproduction of IFN and the expansion of Tph cells. The applicant’s professional goal is to become an independent investigator working in academia in the context of SLE immunopathogenesis. She intends to extend her postdoctoral studies, including evaluating T cell interactions with antigen-presenting cells such as dendritic cells, to propose novel therapeutic approaches.