Abstract 350: The Pro-atherosclerotic Milieu Converts a Sub-population of Murine Peripheral T Regulatory Cells to a Non-suppressive Th1-like Foxp3+IFNγ+ Phenotype.
CD4+ 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-expresses Interferon-γ (IFNγ) has been demonstrated in several models of inflammation. In atherosclerosis, circulating Treg content inversely corresponds with atherogenesis, suggesting that inflammation might affect 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-/- versus C57BL/6 mice. Further phenotyping of Foxp3+IFNγ+ T cells revealed variable expression of Treg and Th1 markers, including low CTLA4, GITR, CD25 expression, equivalent PD1, CD73, FR4, expression and elevated Tbet, CD119, CXCR3, and CCR5 expression. 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, or lineage tracing Foxp3yfp-cre+ R26RtdTomato+ pTregs, to aged Apoe-/- mice. Naïve T cells failed to generate Foxp3+IFNγ+ T cells. In contrast, adoptively transferred Tregs maintained Foxp3 expression (50-60%) or adopted a Foxp3+IFNγ+ T phenotype (40-50%) within the spleen, peri-aortic lymph nodes, and aorta. To test the functionality of IFNγ+ Tregs, we isolated IFNγ+ pTregs, IFNγ- pTregs, and Foxp3GFP+ Tregs for T cell suppression assays. While IFNγ- pTregs and Foxp3GFP+ pTregs were equivalently suppressive, IFNγ+ pTregs failed to adequately suppress T cell proliferation. Together these results demonstrate that atherogenic inflammation affects the maintenance of pTregs, resulting in the generation of a subset of dysfunctional Foxp3+IFNγ+ T cells.
Author Disclosures: M.J. Butcher: None. C.M. McGary: None. A.R. Filipowicz: None. E.V. Galkina: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.