TY - JOUR
T1 - Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B
AU - Nettersheim, Felix Sebastian
AU - Braumann, Simon
AU - Kobiyama, Kouji
AU - Orecchioni, Marco
AU - Vassallo, Melanie
AU - Miller, Jacqueline
AU - Ali, Amal
AU - Roy, Payel
AU - Saigusa, Ryosuke
AU - Wolf, Dennis
AU - Ley, Klaus
AU - Winkels, Holger
N1 - Publisher Copyright:
Copyright © 2022 Nettersheim, Braumann, Kobiyama, Orecchioni, Vassallo, Miller, Ali, Roy, Saigusa, Wolf, Ley and Winkels.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - T cells
KW - adaptive immunity
KW - antigen-specific
KW - atherosclerosis
KW - autoimmune regulator
KW - dextramer
KW - immune tolerance
KW - thymic selection
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U2 - 10.3389/fcvm.2021.812769
DO - 10.3389/fcvm.2021.812769
M3 - Article
AN - SCOPUS:85142752272
SN - 2297-055X
VL - 8
JO - Frontiers in Cardiovascular Medicine
JF - Frontiers in Cardiovascular Medicine
M1 - 812769
ER -