CCR5 ⁺ T-bet ⁺ FoxP3 ⁺ Effector CD4 T Cells Drive Atherosclerosis

Abstract

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.

Regulatory T-Cell Plasticity

“…They blocked effector T-cell expansion and protected against organ-specific inflammation. In the study by Li et al, 16 the adoptive transfer of FoxP3 + CCR5Teff cells into Ccr5 −/− Apoe −/− mice was not protective and was even able to accelerate atherosclerosis to the same extent as conventional effector T cells. Therefore, in vitro and in vivo experiments rule out the possibility that FoxP3 + CCR5Teff cells are Th1-like Tregs and suggest that these cells display an effector T-cell phenotype.…”

“…14 can be induced in the absence of FoxP3. 17 In their study, Li et al 16 have shown that FoxP3 + CCR5Teff cells were able to significantly reduce IFN-γ, IL-4, IL-13, and IL-17A production by effector T cells but were unable to suppress effector T-cell proliferation (Figure). This might be accounted by the inability of CCR5Teff to suppress IL-2 secretion.…”

“…Effector T-cell population expressing FoxP3 had never been described in mice before but had been previously reported in activated human T cells with unstable expression of FoxP3, which did not acquire suppressive function. 20 Li et al 16 − FoxP3 low non-Treg cells. Interestingly, the latter population had the same secretive and functional profile as the mouse CCR5Teff identified by Li et al 16 They both produced IL-2 and IFN-γ and displayed no suppressive functions.…”

“…20 Li et al 16 − FoxP3 low non-Treg cells. Interestingly, the latter population had the same secretive and functional profile as the mouse CCR5Teff identified by Li et al 16 They both produced IL-2 and IFN-γ and displayed no suppressive functions.…”

“…Li et al 16 also explored the role of CCR5 on CD4 + T-cell trafficking. Several studies have previously reported the proatherogenic role of CCR5, but most focused on monocytes.…”