Transforming Growth Factor-β Signaling in T Cells Promotes Stabilization of Atherosclerotic Plaques Through an Interleukin-17-Dependent Pathway

Adaptive immunity has a major impact on atherosclerosis, with pro- and anti-atherosclerotic effects exerted by different subpopulations of T cells. Transforming growth factor-beta (TGF-beta) may promote development either of anti-atherosclerotic regulatory T cells or of T helper 17 (T(H)17) cells, depending on factors in the local milieu. We have addressed the effect on atherosclerosis of enhanced TGF-beta signaling in T cells. Bone marrow from mice with a T cell-specific deletion of Smad7, a potent inhibitor of TGF-beta signaling, was transplanted into hypercholesterolemic Ldlr(-/-) mice. Smad7-deficient mice had significantly larger atherosclerotic lesions that contained large collagen-rich caps, consistent with a more stable phenotype. The inflammatory cytokine interleukin-6 (IL-6) was expressed in the atherosclerotic aorta, and increased mRNA for IL-17A and the T(H)17-specific transcription factor ROR gamma t were detected in draining lymph nodes. Treating Smad7-deficient chimeras with neutralizing IL-17A antibodies reversed stable cap formation. IL-17A stimulated collagen production by human vascular smooth muscle cells, and RORgt mRNA correlated positively with collagen type I and alpha-smooth muscle actin mRNA in a biobank of human atherosclerotic plaques. These data link IL-17A to induction of a stable plaque phenotype, could lead to new plaque-stabilizing therapies, and should prompt an evaluation of cardiovascular events in patients treated with IL-17 receptor blockade.