Abstract 586: CD40L on T Cells is a Major Contributor to Atherosclerosis in Hyperlipidemic Mice

Abstract

Atherosclerosis is a lipid driven chronic inflammatory disease of the arterial wall, involving both innate and adaptive immune responses. Specialized immune cells such as monocytes, B cells, T cells and dendritic cells (DCs) contribute to disease progression or control the inflammatory responses. The CD40-CD40L dyad was identified as an efficient modulator of cellular immune responses. CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily and is activated by CD40 ligand (CD40L). CD40 and CD40L both are expressed on the majority of immune and non-immune cells associated with atherosclerosis. However, the specific contribution of CD40-CD40L signaling on the different single cell types towards atherosclerosis progression remains undefined. Here, we aimed to investigate the cell type-specific mechanisms of CD40-CD40L interactions in atherosclerosis by generating mice with a conditional ablation of CD40L on T cells. Hyperlipidemic mice with a T cell-specific deficiency of CD40L developed significantly smaller atherosclerotic lesions in the ascending after 28 weeks of chow diet, and following 6 weeks of a cholesterol-enriched diet when compared to their littermate controls. Changes in lesion size were accompanied by a modified anti-inflammatory plaque phenotype, characterized by an increased proportion of smooth muscle cells and a reduced number of pro-inflammatory immune cells, such as macrophages and T cells. T cell CD40L-deficient mice displayed systematically reduced expression of pro-inflammatory cytokines such as IL-1β, IL-2, IL-12, and IFNγ, and increased expression of anti-inflammatory cytokines IL-10 and TGFβ. This anti-inflammatory milieu was paralleled a change in the development and activation status of the T cells with mice lacking CD40L on T cells displaying a reduction in the expression of cytokines and gene markers associated with the activation of T cells (e.g., IL-2, CD69). This change was also reflected within the T cell populations which had a reduced proportion of activated effector T cells and an increased ratio of naïve T cells. Thus, our study ascribes CD40L on T cells a central role in atherosclerosis.