The role of T cell response to antigenic ApoB-100 peptides in vaccination strategies against atherosclerosis
Final Report Abstract
The autoimmune response in atherosclerosis with CD4+ T-helper cells and B cell derived antibodies against the main atherosclerosis-related auto-antigen ApoB-100 - the protein backbone of low-density lipoprotein (LDL) particles - has remained enigmatic. It was anticipated, but not proven, that the autoimmune response that accompanies atherosclerosis is pathogenic and only develops in the course of disease. Tools to detect autoreactive CD4+ T cells have not been available in the past. Here, the applicant has developed and validated an MHC-II tetramer of the ApoB auto-peptide TGAYSNASSTESASY corresponding to the mouse ApoB residues 978-993, which allowed to specifically detect ApoB-specific CD4+ T-helper cells. This tool revealed the unexpected existance of a naturally occurring population of ApoB-specific T cells in healthy mice that shared properties with atheroprotective T-regulatory (Treg) cells. ApoB+ Tregs directly prevented atherosclerosis in adoptive transfers in immune-deficient that lacked the competition with other T cells. However, in fully-immunocompetent mice, these cells failed to modulate atherosclerosis. Mechanistically, ApoB+ T cells gradually transformed into Th1 and THl7-like cells with pro-inflammatory and pro-atherogenic gene and protein expression. This pro-inflammatory transformation coincided with the loss of the Treg-defining transcription factor FoxP3 and suggested an instability of ApoB+ Tregs. Atheroprotective vaccination with the corresponding ApoB-peptide protected from atherosclerosis, increased the number of ApoB+ T cells initially, but required the co-existance of ApoB-recognizing B cells and B-cell derived IL-10, a known atheroprotective cytokine. Combined vaccines with ApoB and cognate B cell antigens demonstrated that atheroprotective vaccination did not require B cell derived antibodies against ApoB. Clinically, the number and the extend of pro-inflammatory cytokine secretion of ApoB-reactive T-helper cells correlated clinically with relevant coronary atherosclerosis. The findings suggest that T cell-dependent auto-immunity in the vessel wall is initially protective but lost during disease progression. Consistently, the frequency of a memory-like CD4+ T cell subpopulation identified by single-cell sequencing was highest in healthy arteries. In human carotid plaques, the frequency of this population correlated negatively with future cardiovascular complications. Thus, therapeutically maintaining ApoB-specific T cells and their protective phenotype by immunomodulatory vaccination may represent a future prevention strategy for atherosclerosis.
Publications
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Beyond vascular inflammation--recent advances in understanding atherosclerosis. Cellular and molecular life sciences: CMLS. 2015; 72(20):3853-69
Wolf D, Zirlik A, Ley K
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HGF Guides T Cells into the Heart. Immunity. 2015; 42(6):979-81
Wolf D, Li J, Ley K
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Waking up the stem cell niche: how hematopoietic stem cells generate inflammatory monocytes after stroke. Circulation Research. 2015; 116(3):389-92
Wolf D, Ley K
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Vaccination to Prevent Cardiovascular Disease. Platelets, Haemostasis and Inflammation. December 2017
Wolf D, Gerhardt T, Ley K
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A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nature communications. 2018; 9(1):525
Wolf D, Anto-Michel N, Blankenbach H, Wiedemann A, Buscher K, Hohmann JD, Lim B, Bäuml M, Marki A, Mauler M, Duerschmied D, Fan Z, Winkels H, Sidler D, Diehl P, Zajonc DM, Hilgendorf I, Stachon P, Marchini T, Willecke F, Schell M, Sommer B, von Zur Muhlen C, Reinöhl J, Gerhardt T, Plow EF, Yakubenko V, Libby P, Bode C, Ley K, Peter K, Zirlik A
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Atherosclerosis in the single-cell era. Current opinion in lipidology. 2018; 29(5):389-396
Winkels H, Ehinger E, Ghosheh Y, Wolf D, Ley K
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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; 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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Inflammatory Pathways Regulated by Tumor Necrosis Receptor- Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity. Circulation Research. 2018; 122(5):693-700
Anto Michel N, Colberg C, Buscher K, Sommer B, Pramod AB, Ehinger E, Dufner B, Hoppe N, Pfeiffer K, Marchini T, Willecke F, Stachon P, Hilgendorf I, Heidt T, von Zur Muhlen C, von Elverfeldt D, Pfeifer D, Schüle R, Kintscher U, Brachs S, Ley K, Bode C, Zirlik A, Wolf D
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Immunity and Inflammation in Atherosclerosis. Circulation Research. 2019; 124(2):315-327
Wolf D, Ley K
