Project Details
Projekt
P2: Role of CD4+ T cells in the generation and modulation of GPCR autoimmunity
Subject Area
Rheumatology
Clinical Immunology and Allergology
Clinical Immunology and Allergology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 552470287
Agonistic autoantibodies (Abs) against G-protein coupled receptors (GPCRs), such as the angiotensin II receptor type 1 (AT1R), are one of the hallmark findings in systemic sclerosis (SSc) and are particularly associated with pulmonary arterial hypertension. CD4+ T cells play a central role in initiating and perpetuating pathological immune responses in autoimmune diseases and are considered to contribute to chronic inflammation, fibrosis and vascular disease (VD) in SSc, and also to the pathogenesis of atherosclerosis and cardiovascular diseases. Our previous works support a pivotal role of distinct CD4+ T cell subsets in SSc- and AT1R-associated immune pathologies, in particular Th17, IL-13+ and AT1R+ T cells as drivers and, on the other hand, regulatory T cells (Treg) as modulators of disease processes. However, the precise role of certain T cell subsets and the mechanisms by which T cells contribute to the generation, regulation and modulation of GPCR Abs and to the development of associated immune pathologies are currently unclear. This project is based on the following hypotheses: (1) GPCR-specific CD4+ T cell subsets are required to drive the generation of pathogenic GPCR Abs and contribute to tissue inflammation and vasculopathy in SSc and other VD. (2) GPCR-specific Treg, on the other hand, limit GPCR Abs generation and effector cell activation and are crucial for resolving tissue inflammation and vasculopathy. (3) CD4+ T cells that express the AT1R and other GPCRs are crucial for mediating tissue inflammation and VD through their capacity to migrate into inflamed sites thereby linking GPCR Abs function with tissue pathologies. To address the role of CD4+ T cells in the emergence and modulation of AT1R Abs and associated immune pathologies, we aim to i) identify and delineate the role of antigen-specific versus AT1R-expressing CD4+ T cell subsets including analysis of their TCR repertoire, expression profiles and functionality in peripheral blood and at the sites of AT1R-associated inflammation and ii) address the role of Treg and of T follicular helper cells in modulating AT1R-associated immune responses and pathologies in our stablished mouse models (WP3). We will apply state-of-the-art and advanced techniques in patient samples and mouse models of GPCR-associated VD and inflammation: Findings and approaches derived from these experiments will also be used for evaluating the role of CD4+ T cells in the generation and modulation of other GPCR Abs and their associated pathologies. These efforts will provide detailed and crucial insights into the importance of different CD4+ T cell subsets in generating and modulating immune responses against GPCR and for understanding GPCR-driven immune dysregulation and VD at the level of T cells that includes the identification of novel checkpoints for therapeutic and preventive interventions.
DFG Programme
Research Units
