RESUMO
T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR(-/-) controls. PD-L1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD4(+) and CD8(+) T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD4(+) T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD4(+) T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation.
Assuntos
Antígenos de Superfície/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Aterosclerose/imunologia , Antígeno B7-1/fisiologia , Glicoproteínas de Membrana/fisiologia , Peptídeos/fisiologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Superfície/genética , Aorta/patologia , Proteínas Reguladoras de Apoptose/genética , Aterosclerose/genética , Aterosclerose/patologia , Antígeno B7-1/genética , Antígeno B7-H1 , Colesterol/sangue , Citocinas/sangue , Hipercolesterolemia/metabolismo , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Peptídeos/genética , Fenótipo , Proteína 2 Ligante de Morte Celular Programada 1 , Receptor de Morte Celular Programada 1 , Transdução de SinaisRESUMO
BACKGROUND: PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart. METHODS AND RESULTS: Cytotoxic T-lymphocyte-mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2-deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell-derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2(-/-)], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2(-/-) mice reconstituted with bone marrow from wild-type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency. CONCLUSIONS: Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune-mediated cardiac injury and polymorphonuclear leukocyte inflammation.
Assuntos
Antígeno B7-1/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Células Endoteliais/metabolismo , Glicoproteínas de Membrana/fisiologia , Miocardite/metabolismo , Peptídeos/fisiologia , Animais , Antígeno B7-1/biossíntese , Antígeno B7-1/genética , Antígeno B7-H1 , Linfócitos T CD8-Positivos/patologia , Células Endoteliais/patologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocardite/imunologia , Miocardite/patologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Peptídeos/genética , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses. METHODS AND RESULTS: Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice. CONCLUSIONS: ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Aterosclerose/genética , Aterosclerose/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/biossíntese , Aterosclerose/metabolismo , Células Cultivadas , Feminino , Proteína Coestimuladora de Linfócitos T Induzíveis , Depleção Linfocítica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologiaRESUMO
There is limited published research about the dietary impacts of farmers' markets. We sought to understand whether market managers collect data about markets and to examine the instruments and strategies used. Of the 359 market managers contacted across the United States, representing 543 markets, 185 managers participated in a telephone survey. A subset supplied copies of data collection tools for further analysis. Ninety-three percent of market managers collect data such as customer surveys, vendor applications, customer counts, or demographics. The potential utility of the data collected by mangers and suggestions for study of the dietary impacts of farmers markets are discussed.