Abstract 16015: Loss of Protective Autoimmunity in Atherosclerosis
Background: In atherosclerosis, CD4+ T helper cells recognize auto-antigens including ApoB-100, the main protein in low-density lipoprotein (LDL). However, atherosclerosis-specific, auto-reactive CD4+ T cells have not been detected in vivo.
Methods and Results: We have previously identified several peptides derived from mouse ApoB-100 that bind with high affinity to the MHC class II molecule of C57BL/6 mice (I-Ab). Immunization with these peptides conferred atheroprotection. We designed and validated a new dextramer of a recombinant MHC-II molecule fused to one of these ApoB-100 auto-epitopes, P6, (P6:I-Ab) that enabled detection of low-affinity P6-reactive CD4+ T cells. Using this P6:I-Ab dextramer, we identified a novel population of auto-reactive CD4+ T cells in healthy, young C57BL/6 mice that was predominately differentiated into T-regulatory cells (Tregs). In wildtype mice, this repertoire of T cells was detectable in the thymus at birth and expanded within 28 days in peripheral lymph nodes. In atherosclerotic Apoe-/- mice on a western diet, P6:I-Ab+ CD4+ T cell numbers correlated negatively to the extent of atherosclerotic lesions and eventually disappeared while the mice were aging. Mechanistically, we found enhanced apoptosis in antigen-specific T cells – an effect likely explained by increased T cell exhaustion and expression of its corresponding markers, such as ICOS-1 or PD-1, after persisting antigen-exposure in atherosclerotic mice. In a Treg lineage tracking mouse, Tregs specifically recognizing the ApoB-100 epitope P6 were more likely to lose their defining transcription factor FoxP3 and to turn into pro-atherogenic TH17 T-helper cells. In the plaque, many T cells can be identified as such ex-Tregs, suggesting that atherosclerosis-specific CD4+ T cells that homed to the aorta lost their regulatory capacity and instead further exacerbate atherosclerosis.
Conclusion: Our findings experimentally establish the concept of protective autoimmunity in atherosclerosis: Protective T-regulatory cells specifically recognizing peptide antigens of ApoB-100 exist in naitive mice, temporarily expand, and lose their regulatory phenotype in atherosclerosis.
Author Disclosures: D. Wolf: None. T. Gerhardt: None. S. McArdle: None. L. Baas: None. M. Vassallo: None. T. Dileepan: None. B.E. Hanson: None. K. Tse: None. H. Tse: None. A. Sette: None. M.K. Jenkins: None. K. Ley: None.
- © 2016 by American Heart Association, Inc.