CD40 ligand is selectively expressed on CD4+ T cells and platelets: implications for CD40-CD40L signalling in atherosclerosis.

Atherosclerosis is a degenerative inflammatory disease of the vascular system. Endothelial cells (ECs), smooth muscle cells, and macrophages, key elements in atherosclerosis, all have the potential to express the CD40 receptor and are thus susceptible to potent pro-inflammatory signals by CD40 ligand (CD40L)-bearing cells. CD40L is a TNF-alpha-related membrane protein originally identified on activated T cells. The recent recognition of platelets as an abundant source of CD40L led to a reassessment of the involvement of CD40L in atherosclerosis. In the present report, CD40L(+) T cells were identified in the intima of atherosclerotic tissues within macrophage infiltrates and in areas of neovascularization. These CD40L(+) T cells were CD4(+), CD69(+), but negative for CD8, CD25, CD28, and ICOS. In some specimens, CD40L(+) platelets were identified in the intima and in plaque ruptures. Contrary to previous reports, CD40L was not observed on ECs, smooth muscle cells, and macrophages in atherosclerotic tissues or in vitro at the protein and mRNA levels. Functionally, flow chamber experiments demonstrated that stimulation of ECs via CD40 is sufficient to recruit neutrophils and T cells from whole blood to ECs and suggested that CD40L(+) platelets contribute significantly to the recruitment of inflammatory cells to damaged endothelium in vivo. However, due to the short half-life of platelet CD40L, the chronic CD40L-driven inflammatory component can only be sustained by activated CD4(+) T cells. Contrary to current understanding, the contribution of CD40L to chronic inflammation in atherosclerosis is thus antigen-driven and MHC-dependent. This conclusion has significant therapeutic implications.