Abstract 14742: A Concomitant Switch Towards Th17 And Treg Responses Mediates Atheroprotection In T-bet-deficient Mice
T-box transcription factor (T-bet) is required for Th1 differentiation. A previous study showed that T-bet deficiency in Ldlr-/- mice reduced lesion development, which was associated with a clear Th2 switch. However, no direct evidence was provided to support a role for Th2 in the observed atheroprotection. T-bet expression and IFN-g production also control Th17 and regulatory T cells (Treg) fate, with potentially important consequences on lesion development. While Treg have been consistently shown to mediate atheroprotection, the role of Th17 cells in this context remains hotly debated. Here, we addressed the contribution of Treg and IL17-producing Th17 cells to atheroprotection in mice with reduced T-bet expression. We reconstituted lethally-irradiated male Ldlr-/- mice with bone marrow from control (T-bet+/+ -> Ldlr-/-) or T-bet-/- (T-bet-/- -> Ldlr-/-) mice. After 4 weeks of recovery, mice were put on high fat atherogenic diet for 5 weeks with or without administration of a mouse monoclonal anti-IL17 neutralizing antibody. T-bet-/- -> Ldlr-/- mice showed a significant 50% of T-bet expression compared with T-bet+/+ -> Ldlr-/- mice. As expected, this led to a significant reduction of atherosclerotic lesion size in the aortic root (-38% p=0.0493). The atheroprotective effect was associated with reduced IFN-g production, an enhancement of IL4 but also a substantial increase of Th17. Unexpectedly, concomitant with Th17, we found a marked increase in the percentage of Treg cells in the spleen of T-bet-/- -> Ldlr-/- mice compared with T-bet+/+ -> Ldlr-/- (+25% p=0.0002). While anti-IL17 administration had no effect on T-bet+/+ -> Ldlr-/- mice, neutralization of IL17 blunted the beneficial effect of T-bet insufficiency on atherosclerotic lesion development, showing an atheroprotective role for IL17. Interestingly, IL17 neutralization did not alter the Th2 switch but suppressed the increase of Treg cells in T-bet-/- -> Ldlr-/- mice, suggesting a link between IL17 and Treg differentiation in that context. In conclusion, our results indicate that atheroprotection in T-bet-insufficent mice is independent of the Th2 switch and is mediated by an unsuspected cooperation between Th17 and Treg cells.
- © 2011 by American Heart Association, Inc.