The pro-atherosclerotic milieu promotes the conversion of murine T regulatory cells to a spectrum of Foxp3+IFNγ+ T cell phenotypes. (IRC8P.481)

Abstract

Abstract T cell subsets play diverse roles in inflammation but may also display limited plasticity. The existence of a population of Foxp3+ T regulatory (Treg) cells that co-express Interferon-γ (IFNγ), has been demonstrated in several models of inflammation. In atherosclerosis, circulating Treg content inversely corresponds with atherogenesis, suggesting that inflammation affects peripheral Treg (pTregs) maintenance. Thus, we sought to examine the fate of pTregs within atherosclerotic Apolipoprotein E-deficient (Apoe-/-) mice. Foxp3+IFNγ+ T cells were elevated within the aorta, spleen, and peripheral lymph nodes (PLNs) of atherosclerotic Apoe-/- mice in comparison to C57BL/6 mice. Further phenotyping of Foxp3+IFNγ+ T cells revealed variable expression of both Treg and Th1 markers, including PD1, GITR, CD25, CD73, Tbet, CXCR3, and CCR5. To determine whether Foxp3+IFNγ+ T cells arise from de novo differentiation or peripheral conversion, we performed fate tracking experiments with co-adoptively transferred naïve T cells and pTregs within Apoe-/- mice. In this system, naïve T cells failed to generate Foxp3+IFNγ+ T cells. In contrast, adoptively transferred Tregs lost Foxp3 expression (50%), maintained Foxp3 expression (40-45%), or adopted a Foxp3+IFNγ+ phenotype (5-10%) within all of the tissues examined. Together, these results demonstrate that inflammation during atherogenesis affects the maintenance of pTregs, resulting in the generation of phenotypically diverse Foxp3+IFNγ+ T cells.