Unravelling Treg Plasticity in Atherosclerosis
Final Report Abstract
Regulatory T cells (Tregs) play an important role as anti-inflammatory modulators of atherosclerosis. Mouse models of atherosclerosis demonstrate the vanishing of these cells from atherosclerotic lesions in disease progression. This is in line with several reports describing a reduction in circulating Tregs of patients suffering from acute coronary syndrome. The presence of an autoreactive CD4+ T cell population in atherosclerosis has been proposed by indirect methods or restimulation assays, but a tool allowing direct detection of these cells in atherosclerosis was not available. The host institution specifically designed tools which allow for the detection of T cells recognizing peptides of ApolipoproteinB-100 (ApoB100), a major component of lowdensity lipoprotein and proposed auto-antigen in atherosclerosis. These tools uncovered surprisingly presence of a naturally occurring ApoB-reactive CD4+ T cells in healthy individuals and mice . Their phenotype in homeostasis shared features with atheroprotective Tregs. cells. However, flow cytometric, bulk transcriptome, and single cell RNA sequencing analysis revealed that these ApoB-reactive CD4+ T cells also shared features of other CD4+ T helper cell lineages. This points to a multi-lineage committed and highly plastic cell population. Vaccination with ApoB peptides prevented atherosclerosis in mice by inducing the expansion of ApoB-reactive and IL- 10 producing Tregs. In the course of atherosclerosis in non-vaccinated mice and in individuals with subclinical atherosclerosis or coronary artery disease, ApoB-reactive CD4+ T cells lost Foxp3 expression and transformed into cells with pro-inflammatory features. Simultaneously, while ApoB-reactive CD4+ T cells change their phenotype, the overall immune cell landscape in atherosclerotic aortas changes. High-parametric analysis including single cell RNA sequencing and mass cytometry allowed for the first time for a detailed analysis of the aortic cell landscape in atherosclerosis. The heterogeneity of aortic immune cells is more diverse than expected. The integrated analysis of different data sets demonstrated presence of aortic Tregs, however, the overall CD4 T cell response in atherosclerosis is dominated by subsets with proinflammatory features. This indicates that the initial protective auto-reactive T cell response is lost in the course of atherosclerosis. These results present promising new strategies by stabilizing and expanding ApoB-specific Tregs in atherosclerosis.
Publications
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Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry. Circulation research. 2018 Jun 8;122(12):1675-1688
Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, Hamers AAJ, Cochain C, Vafadarnejad E, Saliba AE, Zernecke A, Pramod AB, Ghosh AK, Anto Michel N, Hoppe N, Hilgendorf I, Zirlik A, Hedrick CC, Ley K, Wolf D
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Regulatory CD4+ T cells Recognize Major Histocompatibility Complex Class II Moleculerestricted Peptide Epitopes of Apolipoprotein B. Circulation. 2018 Sep 11;138(11):1130-1143
Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, Wolf D, Ryden C, Orrechioni M, Dileepan T, Jenkins MK, James EA, Kwok WW, Hanna DB, Kaplan RC, Strickler HD, Durkin HG, Kassaye SG, Karim R, Tien PC, Landay AL, Gange SJ, Sidney J, Sette A, Ley K
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Pathogenic autoimmunity in atherosclerosis evolves from initially protective ApoB-reactive CD4+ T-regulatory cells. Circulation. 2020;142:1279–1293
Wolf D, Gerhardt T, Winkels H, Michel NA, Pramod AB, Ghosheh Y, Brunel S, Buscher K, Miller J, McArdle S, Baas L, Kobiyama K, Vassallo M, Ehinger E, Dileepan T, Ali A, Schell M, Mikulski Z, Sidler D, Kimura T, Sheng X, Horstmann H, Hansen S, Mitre LS, Stachon P, Hilgendorf I, Gaddis D, Hedrick CC, Benedict CA, Peters B, Zirlik A, Sette A, Ley K
