RESUMEN
Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure. Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process. However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking. We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU). We found extensive and complicated changes in the cellular constituents of CDLNs during aging. When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice. Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice. The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs' effects on facilitating the pathogenicity of Th17 cells. Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs. Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.
Asunto(s)
Animales , Ratones , Envejecimiento , Enfermedades Autoinmunes , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Ratones Endogámicos C57BL , Células Th17/metabolismo , Uveítis/patología , VirulenciaRESUMEN
COVID-19, caused by SARS-CoV-2, has recently affected over 300,000 people and killed more than 10,000. The manner in which the key immune cell subsets change and their states during the course of COVID-19 remain unclear. Here, we applied single-cell technology to comprehensively characterize transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19. Compared with healthy controls, in patients in the early recovery stage (ERS) of COVID-19, T cells decreased remarkably, whereas monocytes increased. A detailed analysis of the monocytes revealed that there was an increased ratio of classical CD14++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14++IL1B+ monocytes in the ERS. CD4+ and CD8+ T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naive B cells decreased. Our study identified several novel B cell-receptor (BCR) changes, such as IGHV3-23 and IGHV3-7, and confirmed isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity. Furthermore, integrated analysis predicted that IL-1{beta} and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2 and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting that COVID-19 patients are still vulnerable after hospital discharge. Our identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19. Highlights- The immune response was sustained for more than 7 days in the early recovery stage of COVID-19, suggesting that COVID-19 patients are still vulnerable after hospital discharge. - Single-cell analysis revealed a predominant subset of CD14++ IL1{beta}+ monocytes in patients in the ERS of COVID-19. - Newly identified virus-specific B cell-receptor changes, such as IGHV3-23, IGHV3-7, IGHV3-15, IGHV3-30, and IGKV3-11, could be helpful in the development of vaccines and antibodies against SARS-CoV-2. - IL-1{beta} and M-CSF were discovered as novel mediators of inflammatory cytokine storm, and TNFSF13, IL-2, IL-4, and IL-18 may be beneficial for recovery.
RESUMEN
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Asunto(s)
Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Adulto Joven , Envejecimiento , Genética , Alergia e Inmunología , Betacoronavirus , Linfocitos T CD4-Positivos , Metabolismo , Linaje de la Célula , Ensamble y Desensamble de Cromatina , Infecciones por Coronavirus , Alergia e Inmunología , Síndrome de Liberación de Citoquinas , Alergia e Inmunología , Citocinas , Genética , Susceptibilidad a Enfermedades , Citometría de Flujo , Métodos , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Reordenamiento Génico , Sistema Inmunológico , Biología Celular , Alergia e Inmunología , Inmunocompetencia , Genética , Inflamación , Genética , Alergia e Inmunología , Espectrometría de Masas , Métodos , Pandemias , Neumonía Viral , Alergia e Inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , TranscriptomaRESUMEN
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Asunto(s)
Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Adulto Joven , Envejecimiento , Genética , Alergia e Inmunología , Betacoronavirus , Linfocitos T CD4-Positivos , Metabolismo , Linaje de la Célula , Ensamble y Desensamble de Cromatina , Infecciones por Coronavirus , Alergia e Inmunología , Síndrome de Liberación de Citoquinas , Alergia e Inmunología , Citocinas , Genética , Susceptibilidad a Enfermedades , Citometría de Flujo , Métodos , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Reordenamiento Génico , Sistema Inmunológico , Biología Celular , Alergia e Inmunología , Inmunocompetencia , Genética , Inflamación , Genética , Alergia e Inmunología , Espectrometría de Masas , Métodos , Pandemias , Neumonía Viral , Alergia e Inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , TranscriptomaRESUMEN
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.