Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Июль 6, 2020

Abstract The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation T cells and cytokine production in affected COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, patients’ cell compartment displays several alterations involving naïve, central memory, effector memory terminally differentiated cells, as well regulatory PD1 + CD57 exhausted cells. Significant exist also lineage-specifying transcription factors chemokine receptors. Terminally from proliferate less than those whereas their mitochondria functionality similar CD4 both groups. Patients display significant increases proinflammatory or anti-inflammatory cytokines, including helper type-1 type-2 chemokines galectins; lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 IL-17, the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.

Язык: Английский

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Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

Journal of Clinical Investigation, Год журнала: 2020, Номер 130(9), С. 4694 - 4703

Опубликована: Май 28, 2020

BACKGROUND. Coronavirus disease 19 (COVID-19) is an emerging infectious caused by SARS-CoV-2. Antiviral immune response crucial to achieve pathogen clearance; however, in some patients excessive and aberrant host can lead acute respiratory distress syndrome. The comprehension of the mechanisms that regulate elimination, immunity, pathology essential better characterize progression widen spectrum therapeutic options.

Язык: Английский

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Directed Evolution: Methodologies and Applications

Chemical Reviews, Год журнала: 2021, Номер 121(20), С. 12384 - 12444

Опубликована: Июль 23, 2021

Directed evolution aims to expedite the natural process of biological molecules and systems in a test tube through iterative rounds gene diversifications library screening/selection. It has become one most powerful widespread tools for engineering improved or novel functions proteins, metabolic pathways, even whole genomes. This review describes commonly used diversification strategies, screening/selection methods, recently developed continuous strategies directed evolution. Moreover, we highlight some representative applications nucleic acids, genetic circuits, viruses, cells. Finally, discuss challenges future perspectives

Язык: Английский

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Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

European Journal of Immunology, Год журнала: 2021, Номер 51(12), С. 2708 - 3145

Опубликована: Дек. 1, 2021

Abstract The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes functional assays all major human murine immune cell subsets. Notably, contain helpful tables highlighting differences between cells. Another useful feature this is analysis clinical samples with examples applications in context autoimmune diseases, cancers as well acute chronic infectious diseases. Furthermore, there are detailing tips, tricks pitfalls avoid. All written peer‐reviewed by leading experts immunologists, making an essential state‐of‐the‐art handbook for basic researchers.

Язык: Английский

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Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas

Circulation Research, Год журнала: 2020, Номер 127(3), С. 402 - 426

Опубликована: Июль 16, 2020

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify new subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer innate lymphoid cells-2, CD (cluster of differentiation)-8 T cells form prominent separate immune cell populations aortas. Many CD4 express IL (interleukin)-17 the chemokine CXCR (C-X-C receptor)-6. A small number regulatory helper 1 is identified. Immature naive are present both healthy Our meta-analysis overcomes limitations individual studies that, because their experimental approach, over- or underrepresent certain populations. Mass demonstrate surface phenotype provides valuable information beyond transcriptomes. analysis helps resolve some long-standing controversies field. First,

Язык: Английский

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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(30)

Опубликована: Июль 23, 2021

Foxp3-expressing CD4+CD25+ regulatory T cells (Tregs) constitutively and highly express the immune checkpoint receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism of Treg-mediated suppression, Treg-expressed CTLA-4 down-regulates expression CD80/CD86 costimulatory molecules on antigen-presenting (APCs). Here, we show that facilitated Treg-APC conjugation synapse formation. The synapses thus formed provided stable platform whereby Tregs were able to deplete APCs by extracting them via CTLA-4-dependent trogocytosis. depletion occurred even with solely expressing mutant form lacking cytoplasmic portion required for its endocytosis. trogocytosis also accelerated in vitro vivo passive transfer other membrane proteins lipid from without their significant reduction APC surface. Furthermore, CD80 down-regulation or blockade soluble CTLA-4-immunoglobulin (CTLA-4-Ig), respectively, disrupted cis-CD80/programmed death ligand-1 (PD-L1) heterodimers increased free PD-L1 dendritic (DCs), expanding phenotypically distinct population CD80lo PD-L1hi DCs. Thus, are inhibit cell stimulatory activity reducing This is exert dual suppressive effects responses limiting costimulation naïve increasing available inhibition programmed death-1 (PD-1)-expressing effector cells. Blockade PD-1/PD-L1 combination may therefore synergistically hinder thereby effectively enhancing responses, including tumor immunity.

Язык: Английский

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Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells

Cell, Год журнала: 2020, Номер 181(5), С. 1080 - 1096.e19

Опубликована: Май 1, 2020

Язык: Английский

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Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells

Nature, Год журнала: 2021, Номер 600(7888), С. 295 - 301

Опубликована: Окт. 25, 2021

Язык: Английский

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Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF

Immunity, Год журнала: 2020, Номер 52(2), С. 295 - 312.e11

Опубликована: Янв. 7, 2020

Specialized regulatory T (Treg) cells accumulate and perform homeostatic regenerative functions in nonlymphoid tissues. Whether common precursors for nonlymphoid-tissue Treg exist how they differentiate remain elusive. Using transcription factor nuclear factor, interleukin 3 regulated (Nfil3) reporter mice single-cell RNA-sequencing (scRNA-seq), we identified two precursor stages of 33 (IL-33) receptor ST2-expressing tissue cells, which resided the spleen lymph nodes. Global chromatin profiling revealed a stepwise acquisition accessibility reprogramming toward cell phenotype. Mechanistically, validated Batf as driver molecular program precursors. Understanding this development will help to harness properties therapy.

Язык: Английский

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Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Май 22, 2020

Abstract At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of isotype-switched (Bsm) murine spleen bone marrow, identified according to individual transcriptional signature cell receptor repertoire. A population marginal zone-like located exclusively the spleen, while a quiescent Bsm found marrow. Three further resident populations, present represent transitional follicular B1 cells, respectively. representing 10-20% marrow one qualifying circulating. In all individually dock onto VCAM1 + stromal and, reminiscent T plasma void activation, proliferation mobility.

Язык: Английский

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