Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B

Felix Sebastian Nettersheim; Simon Braumann; Kouji Kobiyama; Marco Orecchioni; Melanie Vassallo; Jacqueline Miller; Amal Ali; Payel Roy; Ryosuke Saigusa; Dennis Wolf; Klaus Ley; Holger Winkels

doi:10.3389/fcvm.2021.812769

Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B

Front Cardiovasc Med. 2022 Jan 13:8:812769. doi: 10.3389/fcvm.2021.812769. eCollection 2021.

Authors

Felix Sebastian Nettersheim^{1

2

3}, Simon Braumann^{1

2}, Kouji Kobiyama³, Marco Orecchioni³, Melanie Vassallo³, Jacqueline Miller³, Amal Ali³, Payel Roy³, Ryosuke Saigusa³, Dennis Wolf⁴, Klaus Ley^{3

5}, Holger Winkels^{1

3}

Affiliations

¹ Department of Cardiology, University Hospital Cologne, Cologne, Germany.
² Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
³ La Jolla Institute for Immunology, La Jolla, CA, United States.
⁴ Department of Cardiology and Angiology I, University Hospital Freiburg, Freiburg, Germany.
⁵ Department of Bioengineering, University of California, San Diego, San Diego, CA, United States.

Abstract

Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4⁺ T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire ^-/- Apoe ^-/- mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4⁺ T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire ^-/- Apoe ^-/- compared to Aire ^+/+ Apoe ^-/-, irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.

Keywords: T cells; adaptive immunity; antigen-specific; atherosclerosis; autoimmune regulator; dextramer; immune tolerance; thymic selection.