Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
1.
Cell ; 185(3): 493-512.e25, 2022 02 03.
Article in English | MEDLINE | ID: mdl-35032429

ABSTRACT

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Complement Activation , Proteome , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Transcriptome , Adult , Aged , Aged, 80 and over , COVID-19/virology , Chemotactic Factors/metabolism , Cytotoxicity, Immunologic , Endothelial Cells/virology , Female , Humans , Lymphocyte Activation , Male , Microvessels/virology , Middle Aged , Monocytes/metabolism , Neutrophils/metabolism , Receptors, IgG/metabolism , Single-Cell Analysis , Young Adult
2.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: mdl-34592166

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
3.
J Cell Biol ; 222(6)2023 06 05.
Article in English | MEDLINE | ID: mdl-37017636

ABSTRACT

Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.


Subject(s)
Cell Differentiation , Colorectal Neoplasms , Oncogenes , Signal Transduction , Humans , Colorectal Neoplasms/genetics , Intestines , Mutation
SELECTION OF CITATIONS
SEARCH DETAIL