Foxp3
+
T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Emerging 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. Here, we addressed whether atherosclerosis impacts Treg plasticity or functionality in
Apoe
-/-
mice and what effect Treg plasticity might have on the pathology of atherosclerosis. We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3
+
Tregs, and the accumulation of an intermediate Th1-like IFNγ
+
CCR5
+
Treg subset (Th1/Tregs) within the arterial wall. Using
Foxp3
Gfp/Gfp
and
Foxp3
Yfp-cre/Yfp-cre
Rosa
tdTomato/tdTomato
lineage tracing mice, we demonstrate that Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than T effector cells. Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Importantly, using
Mir146a
-/-
mice, we demonstrate that plasticity-prone
Mir146
-/-
Tregs fail to reduce atherosclerosis, arterial Th1, or macrophage content in
Apoe
-/-
recipients. Lastly, we utilized single cell RNA-sequencing to gain whole transcriptome information on Th1/Tregs, Treg, and Th1 cells. Th1/Tregs yielded a unique transcriptional phenotype characterized by co-expression of Treg and Th1 lineage genes, and down-regulation of Treg-related genes, including
Ikzf2
,
Ikzf4, Tigit,
and
Lilrb4
. Additionally, an ingenuity pathway analysis further implicates IFNγ, IFNα, IL-2, IL-7, CTLA4, T cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. In conclusion, atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNγ
+
Th1/Tregs that permit further arterial inflammation and atherogenesis.