Abstract 171: Deficiency of the Co-stimulatory Molecule Cd27 Impairs Treg Development and Exacerbates Atherosclerosis.

Atherosclerosis, an inflammatory disease of large arteries, is - through its clinical manifestations stroke and myocardial infarction - the leading cause of morbidity and mortality in the industrialized world. Adaptive immunity and co-stimulatory signals play a pivotal role during all stages of the disease. Recently, regulatory T cells (Treg) were attributed an anti-inflammatory and anti-atherogenic role. The interaction of CD70, a member of the tumor necrosis factor super family with its receptor CD27 modulates Treg development but also affects T cell proliferation, differentiation, and activation at the sites of antigen priming and at effector function. We hypothesized an increased atherosclerotic burden and an exacerbation of disease upon CD27 deficiency. Cd27+/+Apoe-/- or Cd27-/-Apoe-/- bone marrow was transplanted into Apoe-/- recipient mice. After reconstitution, mice were fed a 0.15% high fat/cholesterol diet for 6 weeks. Plaque area at the aortic sinus was increased 2.3-fold in Cd27-/-Apoe-/- chimeras. Plaques contained high amounts of macrophages, which was accompanied by a reduced frequency of aortic (54.1%) and splenic (17.7%) Tregs. Similar results were obtained in 18 wk old Cd27-/-Apoe-/- on a normal chow diet, that also displayed an increase in atherosclerotic plaque area and a 2.5-fold higher plaque macrophage content. In addition, Cd27-/-Apoe-/-mice showed a significant decrease in the abundance of splenic (26%) and aortic (27%) Tregs. Remarkably, 28 week-old Cd27-/-Apoe-/- mice did not exhibit this phenotype, suggesting that CD27 only plays a role in earlier stages of atherosclerosis. Although Cd27-/-Apoe-/- Tregs did not show changes in suppressive or migratory capacity compared to Cd27+/+Apoe-/-, Cd27-deficiency did result in a marked increase in thymic Treg apoptosis. Taken together, our data reveal that deficiency for CD27 impairs thymic Treg development, which thereby exacerbates early and intermediate atherosclerosis by increasing plaque inflammation.