RESUMO
The inducible costimulatory molecule (ICOS) is expressed on activated T cells and participates in a variety of important immunoregulatory functions. After the induction of experimental allergic encephalomyelitis in SJL mice with proteolipid protein (PLP), brain ICOS mRNA and protein were up-regulated on infiltrating CD3+ T cells before disease onset. ICOS blockade during the efferent immune response (9-20 days after immunization) abrogated disease, but blockade during antigen priming (1-10 days after immunization) exacerbated disease. Upon culture with PLP and compared with immunized controls, splenocytes produced either decreased interferon-gamma (IFN-gamma, in efferent blockade) or excessive IFN-gamma (in priming blockade). PLP-specific immunoglobulin G1 was decreased in animals treated with anti-ICOS during antigen priming, but not in other groups.
Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Encefalomielite Autoimune Experimental/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Citocinas/biossíntese , Citocinas/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunoglobulina G/biossíntese , Ligante Coestimulador de Linfócitos T Induzíveis , Proteína Coestimuladora de Linfócitos T Induzíveis , Interferon gama/biossíntese , Camundongos , Proteína Proteolipídica de Mielina/efeitos adversos , Proteína Proteolipídica de Mielina/imunologia , Linfócitos T/imunologia , Regulação para Cima/imunologiaRESUMO
Various adhesion molecules have been implicated in T lymphocyte binding to dermal vascular endothelium in psoriasis vulgaris, but the chemotactic signals that promote subsequent homing into the adjacent dermis and overlying epidermis are poorly defined. We studied chemokine receptor (CCR1-CCR5, CXCR1-CXCR3), chemokine (interferon-gamma inducible protein 10 [IP-10]), monokine induced by interferon-gamma (MIG), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and adhesion molecule (cutaneous lymphocyte antigen [CLA], E-selectin, lymphocyte function-associated antigen-1 [LFA-1], intercellular adhesion molecule-1 [ICAM-1], very late antigen 4 [VLA-4], vascular cell adhesion molecule-1 [VCAM-1], alphaEbeta7, and E-cadherin) expression in psoriasis by immunohistology, flow cytometry, and molecular techniques. CXCR3 and CCR4 were expressed by dermal CD3+ lymphocytes, and their chemokine ligands, IP-10, MIG, TARC, and MDC, were up-regulated in psoriatic lesions. Keratinocytes stimulated with tumor necrosis factor-alpha and interferon-gamma up-regulated expression of IP-10, MIG, and MDC mRNA, whereas dermal endothelial cells, similarly stimulated, up-regulated expression of IP-10, MDC, and TARC mRNA, suggesting that these cell types were sources of the chemokines detected in biopsies. There was enhanced expression of E-selectin, CLA, LFA-1, ICAM-1, VLA-4, VCAM-1, and alphaEbeta7 in psoriatic lesions versus nonlesional skin. Finally, intra-epidermal CLA+ and alphaEbeta7+ T lymphocytes selectively expressed the chemokine receptor CXCR3. Collectively, these data suggest that CXCR3 and CCR4 may be involved in T lymphocyte trafficking to the psoriatic dermis and that CXCR3 is selectively involved in subsequent T cell homing to the overlying epidermis.
Assuntos
Integrinas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular , Psoríase/etiologia , Receptores de Quimiocinas/imunologia , Antígenos de Diferenciação de Linfócitos T , Antígenos de Neoplasias , Biópsia , Células Cultivadas , Quimiocina CCL17 , Quimiocina CCL22 , Quimiocina CXCL10 , Quimiocina CXCL9 , Quimiocinas CC/análise , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Quimiocinas CXC/análise , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Derme/citologia , Derme/imunologia , Derme/metabolismo , Selectina E/imunologia , Selectina E/metabolismo , Endotélio/química , Endotélio/citologia , Endotélio/metabolismo , Expressão Gênica/imunologia , Humanos , Integrina alfa4beta1 , Integrinas/análise , Integrinas/metabolismo , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/metabolismo , Queratinócitos/química , Queratinócitos/citologia , Queratinócitos/metabolismo , Antígeno-1 Associado à Função Linfocitária/análise , Antígeno-1 Associado à Função Linfocitária/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Psoríase/imunologia , Psoríase/patologia , RNA Mensageiro/análise , Receptores CCR4 , Receptores CXCR3 , Receptores de Quimiocinas/metabolismo , Receptores de Retorno de Linfócitos/análise , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Molécula 1 de Adesão de Célula Vascular/análise , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The chemokine receptor CCR5 has recently been described as a co-receptor for macrophage-tropic strains of human immunodeficiency virus (HIV)-1. In this study, using a panel of monoclonal antibodies specific for human CCR5, we show by immunohistochemistry and flow cytometry that CCR5 is expressed by bone-marrow-derived cells known to be targets for HIV-1 infection, including a subpopulation of lymphocytes and monocyte/macrophages in blood, primary and secondary lymphoid organs, and noninflamed tissues. In the central nervous system, CCR5 is expressed on neurons, astrocytes, and microglia. In other tissues, CCR5 is expressed on epithelium, endothelium, vascular smooth muscle, and fibroblasts. Chronically inflamed tissues contain an increased number of CCR5+ mononuclear cells, and the number of immunoreactive cells is directly associated with a histopathological correlate of inflammatory severity. Collectively, these results suggest that CCR5+ cells are recruited to inflammatory sites and, as such, may facilitate transmission of macrophage-tropic strains of HIV-1.