TNF Receptor 2 on CD8+ T cells and TNF receptor 1 on non-CD8+ T cells Contribute Significantly to Chlamydia pneumoniae-Induced Atherosclerosis

Abstract

Abstract Chlamydia pneumoniae is an important cause of community-acquired pneumonia and has been associated with exacerbation of atherosclerosis. A role of TNF-α in Chlamydia pneumoniae (Cpn) induced atherosclerosis has been reported previously; however, the relative contribution of the two cognate receptors of TNF-α, TNF receptor 1 (TNFR1) and TNFR2 had not been studied. In the current study, C57BL/6J (WT) mice, TNFR1, TNFR2 and TNFR1/2 DKO mice were infected intranasally on days 0, 14 and 28 with 1 × 107 IFU of Cpn (AR39) and were fed a high fat (HF) diet throughout the experiment. One group of WT mice were mock infected with PBS as a control. All Cpn-infected KO mice displayed serum anti-Cpn antibody response, splenic cellular Cpn-specific IFN-γ and TNF-α response, and serum total cholesterol levels comparable to infected WT animals. On day 100 following infection, Cpn infected TNFR1, TNFR2 and TNFR1/2 DKO mice displayed significantly reduced atherosclerotic pathology compared to infected WT mice, and at levels comparable to mock-infected WT animals., suggesting that TNFR1 and TNFR2 play a significant role in Cpn-induced atherosclerosis. We demonstrated recently that CD8+ T cells induce Cpn-mediated atherosclerosis; therefore, we further investigated the role of TNFR1 and TNFR2 on CD8+ T cells in pathogenesis. TNFR2 KO mice, not TNFR1 KO mice, replete with WT CD8+ T cells displayed enhancement of atherosclerotic pathology to levels observed in Cpn-infected WT animals. Collectively, these results demonstrate that TNFR2 on CD8+ T cells and TNFR1 on non-CD8+ T cells contribute significantly to Chlamydia pneumoniae induced atherosclerosis.