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
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.