Abstract 385: Conversion of Established Murine Inducible T Regulatory Cells to Foxp3+IFN?+ T Cells in Atherosclerosis Occurs in an IL-12 Dependent Manner
In inflammation, T cell subsets are known to play diverse roles and recent evidence suggests that T helper cells display limited plasticity under specific stimuli. Evidence indicates that a decrease in the number of circulating Tregs corresponds with atherogenesis, and the existence of a population of Foxp3+ T regulatory cells that co-expresses inflammatory cytokines such as Interleukin-17A (IL-17A) and Interferon γ (IFNγ) has been demonstrated in models of inflammation. However, the cellular precursors and mechanisms underlying the generation of Foxp3+IL-17A+ and Foxp3+IFNγ+ T cells are unclear. Thus, we sought to study the fate of T regulatory cells during atherogenesis within 12 week western diet (WD)-fed Apolipoprotein E-deficient (Apoe-/-) mice. Apoe-/- mice have a population of Foxp3+IFNγ+ T regulatory cells within the aorta, spleen, peripheral lymph nodes (PLNs), peri-aortic LNs (PALNs), and mesenteric LNs (MLNs). To determine whether Foxp3+IFNγ+ Tregs arise from de novo differentiating naïve T cells or established Tregs, we performed a series of fate tracking experiments with co-adoptively transferred naïve T cells and inducible T regs in Apoe-/- mice. Both adoptively transferred T regs and naïve T cells were present in the blood and emigrated to the aorta, spleen, PLNs, MLNs, and PALNs of Apoe-/- mice. While naïve T cells were present in the tissues examined, they failed to appreciably differentiate to effector T cell fates. In contrast, half of the adoptively transferred Treg cells lost the expression of Foxp3 within all of the tissues examined. The remaining T regs maintained Foxp3 expression (40-45% of transferred Tregs) or adopted a Foxp3+IFNγ+ phenotype (5-10%). To assess how established T reg cells may convert to Foxp3+IFNγ+ T cells, in vitro differentiated iTregs were maintained in Treg conditions with or without IL-12 and assessed by flow cytometry. iTregs cultured without IL-12 did not become Foxp3+IFNγ+ cells. However in iTreg cultures supplemented with IL-12, 10% of Foxp3+ Tregs co-expressed IFNγ. Together, these results suggest that the pro-inflammatory conditions during atherogenesis affect the maintenance of established Treg cells, resulting in the loss of Foxp3 expression or the generation of Foxp3+IFNγ+ Tregs.
- © 2013 by American Heart Association, Inc.