RESUMO
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
Assuntos
Antígenos Virais/imunologia , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito T/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Reino Unido , Vacinas Virais/imunologiaRESUMO
Using a specific antibody, we found that expression of the viral restriction factor IFITM3 differs across cell types within the immune compartment with higher expression in myeloid rather than lymphoid cells. IFITM3 expression was increased following IFN stimulation, mostly type I, in immune cells, with the exception of T cells.
Assuntos
Antivirais/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células A549 , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Linfócitos/metabolismoRESUMO
Human leukocyte antigen HLA-B alleles have better protective activity against HIV-1 than HLA-A alleles, possibly due to differences in HLA-restricted HIV-1-specific CD8+ cytotoxic T lymphocyte (CTL) function, but the mechanism is unknown. HIV-1 negative regulatory factor (Nef) mediates down-regulation of surface expression of class I HLA (HLA-I) and may therefore impair immune recognition by CTL. Because of sequence differences in the cytoplasmic domains, HLA-A and -B are down-regulated by Nef but HLA-C and -E are not affected. However, the latter are expressed at low levels and are not of major importance in the CTL responses to HIV-1. Here, we compared the role of the cytoplasmic domains of HLA-A and -B in Nef-mediated escape from CTL. We found HLA-B cytoplasmic domains were more resistant to Nef-mediated down-regulation than HLA-A cytoplasmic domains and demonstrated that these differences affect CTL recognition of virus-infected cells in vitro. We propose that the relative resistance to Nef-mediated down-regulation by the cytoplasmic domains of HLA-B compared with HLA-A contributes to the better control of HIV-1 infection associated with HLA-B-restricted CTLs.
Assuntos
Regulação para Baixo/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Alelos , Sequência de Aminoácidos , Linhagem Celular , Citoplasma/imunologia , Epitopos/imunologia , Infecções por HIV/virologia , Antígenos HLA-A/química , Antígenos HLA-A/genética , Antígenos HLA-B/química , Antígenos HLA-B/genética , Antígeno HLA-B7/imunologia , Antígenos HLA-C/química , Antígenos HLA-C/imunologia , Humanos , Dados de Sequência Molecular , Polimorfismo Genético , Estrutura Terciária de Proteína , Proteínas Recombinantes/imunologia , Alinhamento de Sequência , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
The prevalence and incidence of cancers has risen over the last decade. Available treatments have improved outcomes, yet mortality and morbidity remain high, creating an urgent demand for personalized and new therapy targets. Interferon induced transmembrane protein (IFITM3) is highly expressed in cancers and is a marker of poor prognosis. In this review, we discuss recent advances in IFITM3 biology, the regulatory pathways, and its function within cancer as part of immunity and maintaining stemness. Overexpression of IFITM3 is likely an indirect effect of ongoing inflammation, immune and cancer epithelial-to-mesenchymal (EMT) related pathways i.e., interferons, TGF-ß, WNT/ß-catenin, etc. However, IFITM3 also influences tumorigenic phenotypes, such as cell proliferation, migration and invasion. Furthermore, IFITM3 plays a key role in cancer growth and maintenance. Silencing of IFITM3 reduces these phenotypes. Therefore, targeting of IFITM3 will likely have implications for potential cancer therapies.
RESUMO
COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.
RESUMO
OBJECTIVE: Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) co-infection is recognized as a major cause of morbidity and mortality among HIV-1 infected patients. Our understanding of the impact of HIV infection on HCV specific immune responses and liver disease outcome is limited by the heterogeneous study populations with genetically diverse infecting viruses, varying duration of infection and anti-viral treatment. METHODS: Viral-specific immune responses in a cohort of 151 HCV mono- and HIV co-infected former plasma donors infected with a narrow source of virus were studied. HCV and HIV specific T cell responses were correlated with clinical data. RESULTS: HIV-1 accelerated liver disease progression and decreased HCV specific T cell immunity. The magnitude of HCV specific T cell responses inversely correlated with lower HCV RNA load and reduced liver injury as assessed by non-invasive markers of liver fibrosis. HIV co-infection reduced the frequency of HCV specific CD4+ T cells with no detectable effect on CD8+ T cells or neutralizing antibody levels. CONCLUSION: Our study highlights the impact of HIV co-infection on HCV specific CD4+ T cell responses in a unique cohort of patients for both HCV and HIV and suggests a crucial role for these cells in controlling chronic HCV replication and liver disease progression.