Adaptive Immunity in Human Atherosclerosis: Understanding its Cellular Basis to Define Novel Immunomodulatory Therapies

ended

Atherosclerosis is a chronic immune disease of arteries that causes vessel-narrowing atherosclerotic plaques. Its acute complications, myocardial infarction and stroke, are the leading causes of death worldwide. Atherosclerosis is accompanied by an inflammatory and autoimmune response with CD4+ T-helper cells that recognize self-antigens, including ApoB-100 (ApoB), the main protein in low-density lipoprotein (LDL) cholesterol. Although their existence has been inferred from indirect evidence, the existence and function of atherosclerosis-specific, self-reactive CD4+ T cells on a single-cell level remains elusive. In particular, it is unclear whether these are pro- or anti-inflammatory. Preliminary data suggest the existence of a natural pool of ApoB-reactive T-helper cells that share properties with atheroprotective T-regulatory cells but transform into pathogenic T-effector cells in the natural course of disease. This proposal aims to explore this loss of protective immunity on a cellular and function level. It employs novel tools to detect antigen-specific T cells in vivo by MHC-II multimers, mass cytometry (CyTOF), single cell RNA-sequencing (scRNA-seq), lineage-tracing mouse models, and live cell imaging. Based on the anticipated findings, this study will define a map of auto-reactive T-helper cell phenotypes in a temporal, spatial, and functional dimension. These insights will be used to identify novel immunomodulatory strategies to therapeutically stabilize the population of protective ApoB-specific T-helper cells, or to prevent their transformation into pathogenic T cell phenotypes by adoptive cells transfers, vaccination, or cytokine-blockade. In clinical association studies, a direct correlation of auto-immunity and clinical atherosclerosis will be tested. This proposal will decipher traits of protective immunity in atherosclerosis and help to build the conceptual framework to define novel therapeutic strategies for patients.