| First Author | Butcher MJ | Year | 2016 |
| Journal | Circ Res | Volume | 119 |
| Issue | 11 | Pages | 1190-1203 |
| PubMed ID | 27635087 | Mgi Jnum | J:254054 |
| Mgi Id | MGI:6099807 | Doi | 10.1161/CIRCRESAHA.116.309764 |
| Citation | Butcher MJ, et al. (2016) Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNgamma+ Th1/Tregs. Circ Res 119(11):1190-1203 |
| abstractText | RATIONALE: Forkhead box P3(+) T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. OBJECTIVE: Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe(-)(/-) mice, and what effect Treg plasticity might have on the pathology of atherosclerosis. METHODS AND RESULTS: We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3(+) Tregs and the accumulation of an intermediate Th1-like interferon (IFN)-gamma(+)CCR5(+) Treg subset (Th1/Tregs) within the aorta. Importantly, Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than from T-effector cells. We show that Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Using an adoptive transfer system and plasticity-prone Mir146a(-/-) Tregs, we demonstrate that elevated IFNgamma(+) Mir146a(-/-) Th1/Tregs are unable to adequately reduce atherosclerosis, arterial Th1, or macrophage content within Apoe(-/-) mice, in comparison to Mir146a(+/+) Tregs. Finally, via single-cell RNA-sequencing and real-time -polymerase chain reaction, we show that Th1/Tregs possess a unique transcriptional phenotype characterized by coexpression of Treg and Th1 lineage genes and a downregulation of Treg-related genes, including Ikzf2, Ikzf4, Tigit, Lilrb4, and Il10. In addition, an ingenuity pathway analysis further implicates IFNgamma, IFNalpha, interleukin-2, interleukin-7, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), T-cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. CONCLUSIONS: Atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNgamma(+) Th1/Tregs that may permit further arterial inflammation and atherogenesis. |
