RESUMEN
BACKGROUND & AIMS: CD100 is constitutively expressed on T cells and can be cleaved from the cell surface by matrix metalloproteases (MMPs) to become soluble CD100 (sCD100). Both membrane-bound CD100 (mCD100) and sCD100 have important immune regulatory functions that promote immune cell activation and responses. This study investigated the expression and role of mCD100 and sCD100 in regulating antiviral immune responses during HBV infection. METHODS: mCD100 expression on T cells, sCD100 levels in the serum, and MMP expression in the liver and serum were analysed in patients with chronic HBV (CHB) and in HBV-replicating mice. The ability of sCD100 to mediate antigen-presenting cell maturation, HBV-specific T cell activation, and HBV clearance were analysed in HBV-replicating mice and patients with CHB. RESULTS: Patients with CHB had higher mCD100 expression on T cells and lower serum sCD100 levels compared with healthy controls. Therapeutic sCD100 treatment resulted in the activation of DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses, and accelerated HBV clearance, whereas blockade of its receptor CD72 attenuated the intrahepatic anti-HBV CD8 T cell response. Together with MMP9, MMP2 mediated mCD100 shedding from the T cell surface. Patients with CHB had significantly lower serum MMP2 levels, which positively correlated with serum sCD100 levels, compared with healthy controls. Inhibition of MMP2/9 activity resulted in an attenuated anti-HBV T cell response and delayed HBV clearance in mice. CONCLUSIONS: MMP2/9-mediated sCD100 release has an important role in regulating intrahepatic anti-HBV CD8 T cell responses, thus mediating subsequent viral clearance during HBV infection. LAY SUMMARY: Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. The clearance of HBV relies largely on an effective T cell immune response, which usually becomes dysregulated in chronic HBV infection. Our study provides a new mechanism to elucidate HBV persistence and a new target for developing immunotherapy strategies in patients chronically infected with HBV.
Asunto(s)
Antígenos CD , Linfocitos T CD8-positivos/inmunología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica , Inmunidad Celular/inmunología , Hígado , Metaloproteinasa 2 de la Matriz/inmunología , Metaloproteinasa 9 de la Matriz/inmunología , Semaforinas , Animales , Antígenos CD/sangre , Antígenos CD/inmunología , Perfilación de la Expresión Génica , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Hígado/inmunología , Hígado/virología , Activación de Linfocitos/inmunología , Ratones , Semaforinas/sangre , Semaforinas/inmunologíaRESUMEN
In this study, we examined the impact of the rs9264942 single-nucleotide polymorphism, previously shown to be associated with human immunodeficiency virus infection status and HLA-C expression, on the hepatitis C virus status in 359 people who inject drugs (PWID). The linkage of rs9264942 alleles to HLA-C antigens assigned to different expression levels was confirmed. Multivariate analysis revealed the age (P = .003) and the rs9264942 genotype (P = .006) to be independent factors for the classification to the PWID groups. Our study showed that the presence of the rs9264942 C/C genotype was associated with persistent seronegativity.
Asunto(s)
Anticuerpos Antivirales/sangre , Predisposición Genética a la Enfermedad , Antígenos HLA-C/genética , Hepatitis C/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C/etiología , Hepatitis C/inmunología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/aislamiento & purificación , Factores de Riesgo , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto JovenRESUMEN
BACKGROUND & AIMS: Despite continuous high-risk behavior, a subgroup among people who inject drugs (PWID) remains seronegative for hepatitis C virus (HCV) suggesting that a state of "natural resistance" to HCV Infection may exist. Homozygosity for KIR2DL3 and its ligand HLA-C1 group alleles has been associated with control of HCV infection, however, the mechanism mediating this protective effect remained unclear. METHODS: Peripheral NK cells from PWID (n=104) were phenotypically and functionally characterized by multicolor flow cytometry. Expression levels of the NK cell receptor ligands were analysed in liver biopsies and primary human hepatocytes. RESULTS: HCV seronegative PWID (n=34) had increased levels of KIR2DL3(+)NKG2A(-) NK cells compared to healthy controls (n=10; p<0.001) and PWID with chronic (n=38; p<0.001) or resolved infection (n=37; p<0.001). There was an inverse correlation between the frequency of KIR2DL3(+) and NKG2A(+) NK cells (r=-0.53; p<0.0001). Importantly, expression of HLA-E, the ligand for NKG2A, was significantly upregulated in liver biopsies of HCV infected patients (n=51) compared to HBV infected patients (n=22; p<0.01) and correlated with HCV viral load (r=0.32; p<0.0029). In functional analyses KIR2DL3(-)NKG2A(+) NK cells but not KIR2DL3(+)NKG2A(-) NK cells were significantly inhibited by HLA-E ligation. Accordingly, interferon gamma secretion of NK cells from PWID with chronic infection but not from HCV seronegative PWID was significantly suppressed in the presence of HLA-E. CONCLUSIONS: KIR2DL3(+)NKG2A(-) NK cells are not sensitive to HLA-E-mediated inhibition and may thereby control early HCV infection prior to seroconversion and result in an apparent state of "natural resistance" to HCV in PWID.
Asunto(s)
Hepacivirus , Hepatitis C/prevención & control , Inmunidad Innata , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Subfamília C de Receptores Similares a Lectina de Células NK/deficiencia , Receptores KIR2DL3/metabolismo , Abuso de Sustancias por Vía Intravenosa , Adulto , Alelos , Biopsia , Estudios de Casos y Controles , Femenino , Hepacivirus/fisiología , Hepatitis C/metabolismo , Hepatitis C/patología , Antígenos de Histocompatibilidad Clase I/metabolismo , Homocigoto , Humanos , Hígado/patología , Masculino , Fenotipo , Asunción de Riesgos , Replicación Viral , Antígenos HLA-ERESUMEN
Dysfunction of CD8+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus-specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells.