Reducing T Cell-Mediated Cardiac Injury With Cpg Oligodeoxynucleotides

Lymphocytic myocarditis is a common condition associated with both infectious diseases and immunological disorders, and is often associated with severe morbidity and mortality, but few effective treatments. In many cases, the pathophysiology involves a failure of central and/or peripheral immune tolerance leading to a cardiac-specific autoimmune T cell response. Previous studies indicate that the PD-1:PD-L1 axis plays an important role in limiting inflammation in the heart. CpG ODN are TLR9 agonists with known immunoregulatory capacity, in part through their potent induction of type I IFN, a known inducer of PD-L1. In this study, we used human tissue to determine the signature of PD-L1 expression in myocarditis. Furthermore, we investigated the in vitro activity of CpG ODN as an inducer of PD-L1 in the heart, and tested if this activity is dependent on type I IFN. Lastly, we sought to establish the cardioprotective potential of CpG ODN in a CD8+ T cell-mediated adoptive transfer model of myocarditis in mice. Myocarditic human hearts demonstrate elevated PD-L1 relative to healthy hearts, indicating a possible feedback inhibition on inflammation of translational relevance. CpG ODN robustly upregulates PD-L1 and interferon-related genes in the myocardium, though our data is equivocal as to whether this is a type I IFN-dependent process. Pretreatment of mice with CpG ODN significantly reduced the extent of CD8+ T cell-medaited disease as measured by both histology and serology. Though results did not reach statistical significance, preliminary data suggests that this cardioprotection may not be fully dependent upon PD-1:PD-L1 activity. CpG ODN is known to have other immunoregulatory properties, and our data on gene expression in hearts of treated mice suggest other regulatory mechanisms by which CpG ODN may regulate autoimmunity in the heart. Irrespective of the mechanism of action, this study provides evidence of the possible therapeutic utility of CpG ODN as a targeted therapy for myocarditis

IL-23R deficiency does not impact atherosclerotic plaque development in mice

Background--Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. Methods and Results--We used heterozygous Ldlr-/-Il23reGFP/WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr-/-Il23reGFP/eGFP (Ldlr-/- Il23r-/-) mice to investigate the effect of lack of IL-23R in atherosclerosis. We demonstrate the presence of relatively rare IL-23R-expressing cells in lymphoid tissue and aorta (≈0.1-1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high-fat diet, production of IL-17, but not interferon-c, by CD4+ T cells and other lymphocytes was reduced in Ldlr-/- Il23r-/- compared with Ldlr-/-controls. However, Ldlr-/- and Ldlr-/-Il23r-/- mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL-23R-deficient CD4+ T cells to lymphopenic Ldlr-/-Rag1-/- resulted in dramatically reduced IL-17-producing T cells but did not reduce atherosclerosis, compared with transfer of IL-23R-sufficient CD4+ T cells. Conclusions--These data demonstrate that loss of IL-23R does not affect development of experimental atherosclerosis in LDLrdeficient mice, despite a role for IL-23 in differentiation of IL-17-producing T cells

Increased lymphocyte activation and atherosclerosis in CD47-deficient mice

CD47, also known as integrin-associated protein (IAP), is a transmembrane protein with multiple biological functions including regulation of efferocytosis and leukocyte trafficking. In this study we investigated the effect of CD47-deficiency on atherosclerosis using a model of adeno-associated virus (AAV)-induced hypercholesterolemia. We observed increased plaque formation in CD47 null mice compared to wild-type controls. Loss of CD47 caused activation of dendritic cells, T cells and natural killer (NK) cells, indicating an important role for CD47 in regulating immunity. In particular, Cd47 deficiency increased the proportion of IFN-γ producing CD90+ NK cells. Treatment with depleting anti-NK1.1 monoclonal antibody (mAb), but not depleting anti-CD4/CD8 mAbs, equalized atherosclerotic burden, suggesting NK cells were involved in the enhanced disease in Cd47 deficient mice. Additional studies revealed that levels of CD90+ and IFN-γ+ NK cells were expanded in atherosclerotic aorta and that CD90+ NK cells produce more IFN-γ than CD90- NK cells. Finally, we demonstrate that anti-CD47 (MIAP410) causes splenomegaly and activation of DCs and T cells, without affecting NK cell activation. In summary, we demonstrate that loss of CD47 causes increased lymphocyte activation that results in increased atherosclerosis

A Cdc42 Activation Cycle Coordinated by PI 3-Kinase during Fc Receptor-mediated Phagocytosis

During Fc receptor-mediated phagocytosis in macrophages, PI 3-kinase mediates transitions in the signaling by Rho-family GTPases. Receptor-activated Cdc42 increases PI 3-kinase activity. Increased 3′ phosphoinositide concentrations in phagocytic cups then deactivate Cdc42