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- W2760846564 abstract "Background: In atherosclerosis, CD4 + T helper cells recognize auto-antigens including ApoB, the main protein in low-density lipoprotein (LDL). However, atherosclerosis-specific, auto-reactive CD4 + T cells have not been detected in vivo , and their function is unknown. Methods and Results: We have previously identified peptides derived from mouse ApoB that bind with high affinity to the MHC class II molecule of C57BL/6 mice (I-A b ). We designed and validated a new multimer of a recombinant MHC-II molecule fused to one ApoB auto-epitopes, P6 (TGAYSNASSTESASY, P6:I-A b ), that enabled detection of low-affinity, P6-reactive CD4 + T cells. Using this P6:I-A b multimer, we identified ApoB-reactive CD4 + T cells in healthy, young C57BL/6 mice that were predominately differentiated T-regulatory cells (T regs ) and expressed IL-10, a known atheroprotective cytokine. This population was detectable in lymph nodes and already showed a memory phenotype in young animals without atherosclerosis. In Apoe -/- mice, adoptively transferred ApoB P6-specific T regs accumulated in the aorta and draining lymph nodes and gave rise to pathogenic T H 1 and T H 17 cells. This phenotypic switch was caused by enhanced plasticity of antigen-specific T regs as evidenced by multiple clusters of intermediate T reg -T eff phenotypes in single cell RNA sequencing of 4485 antigen-specific CD4 + T cells. In the plaque, many T cells were ex-T regs as identified by a FoxP3 lineage tracker mouse, suggesting that atherosclerosis-specific CD4 + T cells lost their regulatory capacity. Vaccination with P6 maintained a protective phenotype in antigen-specific T regs and protected from atherosclerosis. In humans, ApoB-specific CD4 + T cells from atherosclerotic patients showed the same cytokine patterns found in mouse CD4 + T cells, suggesting that autoimmunity to ApoB is protective first, but later gives rise to a pathogenic CD4 + T cell response that aggravates atherosclerosis. Conclusion: Protective T-regulatory cells recognizing peptide antigens of ApoB exist in naïve mice, protect against atherosclerosis, but convert into pathogenic T H 1 and -17 cells during the natural course of disease in mice and humans. These results call for immunomodulatory therapies to maintain protective autoimmunity." @default.
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- W2760846564 date "2017-05-01" @default.
- W2760846564 modified "2023-09-23" @default.
- W2760846564 title "Abstract 44: Failure of Protective Autoimmunity in Mouse and Human Atherosclerosis" @default.
- W2760846564 doi "https://doi.org/10.1161/atvb.37.suppl_1.44" @default.
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