Abstract 12807: T Cell Co-Stimulation by CD28-CD80/86 and Its Negative Regulator CTLA-4 strongly Influence Accelerated Atherosclerosis Development

Background T lymphocytes play a central role in the inflammatory immune response responsible for native atherosclerosis. Their involvement is suggested in accelerated atherosclerosis development after vascular injury, although their true contribution is unknown. We investigated the roles of the CD28-CD80/86 co-stimulatory and CTLA-4 co-inhibitory pathways responsible for T cell activation status in accelerated atherosclerosis. Methods and Results To investigate the role of T cells and the CD28-CD80/86 co-stimulatory and CTLA-4 co-inhibitory pathways, we used a well-established femoral artery cuff mouse model to induce intimal thickening and found a significant reduction in SMC-rich intimal lesions in both CD4 -/- and CD80 -/- CD86 -/- mice compared to controls. T cell CTLA-4 expression in the operated arterial segments occurred 3d after injury. Systemic treatment with abatacept, a soluble CTLA-4Ig fusion protein that prevents CD28-CD80/86 co-stimulatory T cell activation, significantly prevented intimal thickening. Next, we studied the effects of abatacept in Western-type diet fed hypercholesterolemic ApoE3*Leiden mice. This significantly reduced accelerated atherosclerosis development by preventing both CD4 and CD8 T cell activation, indicated by significantly smaller splenic fractions of activated KLRG1+, PD1+, CD69+, CTLA-4+ and regulatory CD25+FoxP3+ T cells. This resulted in significantly lowered plasma concentration of interferon γ. Draining local iliac lymph node T cell fractions however remained unaffected. The important role of the CTLA-4 co-inhibitory pathway was confirmed in vivo using CTLA-4 blocking antibodies, which strongly increased vascular lesion size in hypercholesterolemic ApoE3*Leiden mice. Conclusions T cell co-activation through the CD28-CD80/86 pathway is vital for post-interventional accelerated atherosclerosis development and is strongly negatively regulated by CTLA-4 co-inhibition.