CCR5+T-bet+FoxP3+ Effector CD4 T Cells Drive Atherosclerosis
Rationale: CD4 T cells are involved in the pathogenesis of atherosclerosis, but atherosclerosis-specific CD4 T cells have not been described. Moreover, the chemokine(s) that regulate T cell trafficking to the atherosclerotic lesions are also unknown.
Objective: In Apoe-/- mice with mature atherosclerotic lesions (5 months of high fat diet), we find that most aortic T cells express CCR5 and IFN-γ with a unique combination of cell surface markers (CD4+CD25-CD44hiCD62Llo) and transcription factors (FoxP3+T-bet+). We call these cells CCR5Teff. We investigated the role of CCR5 in regulating T cell homing to the atherosclerotic aorta and the functionality of the CCR5Teff cells.
Methods and Results: CCR5Teff cells are exclusively found in the aorta and para-aortic lymph nodes (paLNs) of Apoe-/- mice. They do not suppress T cell proliferation in vitro and are less potent than regulatory T cells (Tregs) at inhibiting cytokine secretion. Blocking or knocking out CCR5 or its ligand CCL5 significantly blocks T cell homing to atherosclerotic aortas. Transcriptomic analysis shows that CCR5Teff cells are more similar to effector T cells than to Tregs. They secrete IFN-γ, IL-2, IL-10 and TNF. Adoptive transfer of these CCR5Teff cells significantly increases atherosclerosis.
Conclusions: CCR5 is specifically needed for CD4 T cell homing to the atherosclerotic plaques. CCR5+CD4 T cells express an unusual combination of transcriptional factors, FoxP3 and T-bet. Although CCR5Teff express FoxP3, we showed that they are not regulatory and adoptive transfer of these cells exacerbates atherosclerosis.
- Received March 1, 2016.
- Revision received March 22, 2016.
- Accepted March 28, 2016.