Abstract:
:Quantitative mass spectrometry reveals how CD4+ and CD8+ T cells restructure proteomes in response to antigen and mammalian target of rapamycin complex 1 (mTORC1). Analysis of copy numbers per cell of >9,000 proteins provides new understanding of T cell phenotypes, exposing the metabolic and protein synthesis machinery and environmental sensors that shape T cell fate. We reveal that lymphocyte environment sensing is controlled by immune activation, and that CD4+ and CD8+ T cells differ in their intrinsic nutrient transport and biosynthetic capacity. Our data also reveal shared and divergent outcomes of mTORC1 inhibition in naïve versus effector T cells: mTORC1 inhibition impaired cell cycle progression in activated naïve cells, but not effector cells, whereas metabolism was consistently impacted in both populations. This study provides a comprehensive map of naïve and effector T cell proteomes, and a resource for exploring and understanding T cell phenotypes and cell context effects of mTORC1.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Howden AJM,Hukelmann JL,Brenes A,Spinelli L,Sinclair LV,Lamond AI,Cantrell DAdoi
10.1038/s41590-019-0495-xsubject
Has Abstractpub_date
2019-11-01 00:00:00pages
1542-1554issue
11eissn
1529-2908issn
1529-2916pii
10.1038/s41590-019-0495-xjournal_volume
20pub_type
杂志文章abstract::Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR)...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/86302
更新日期:2001-04-01 00:00:00
abstract::After homing to lymph nodes, CD8+ T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinet...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1559
更新日期:2008-03-01 00:00:00
abstract::CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release-activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which beta-galactosidase activity 'reporte...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1550
更新日期:2008-01-01 00:00:00
abstract::Natural killer T cells (NKT cells) have stimulatory or inhibitory effects on the immune response that can be attributed in part to the existence of functional subsets of NKT cells. These subsets have been characterized only on the basis of the differential expression of a few transcription factors and cell-surface mol...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3437
更新日期:2016-06-01 00:00:00
abstract::Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to i...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/87766
更新日期:2001-05-01 00:00:00
abstract::Mouse conventional dendritic cells (cDCs) can be classified into two functionally distinct lineages: the CD8α(+) (CD103(+)) cDC1 lineage, and the CD11b(+) cDC2 lineage. cDCs arise from a cascade of bone marrow (BM) DC-committed progenitor cells that include the common DC progenitors (CDPs) and pre-DCs, which exit the ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3200
更新日期:2015-07-01 00:00:00
abstract::FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3835
更新日期:2017-11-01 00:00:00
abstract::Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Here we profiled the genome-wide histone modification...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3706
更新日期:2017-05-01 00:00:00
abstract::Toxoplasma gondii is a common protozoan parasite that infects up to one third of the world's population. Notably, very little is known about innate immune sensing mechanisms for this obligate intracellular parasite by human cells. Here, by applying an unbiased biochemical screening approach, we show that human monocyt...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-018-0250-8
更新日期:2019-01-01 00:00:00
abstract::We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of ma...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1001-962
更新日期:2001-10-01 00:00:00
abstract::Mycobacterium tuberculosis PtpA, a secreted tyrosine phosphatase essential for tuberculosis pathogenicity, could be an ideal target for a drug against tuberculosis, but its active-site inhibitors lack selectivity over human phosphatases. Here we found that PtpA suppressed innate immunity dependent on pathways of the k...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3096
更新日期:2015-03-01 00:00:00
abstract::By genetically ablating IkappaB kinase (IKK)-mediated activation of the transcription factor NF-kappaB in the B cell lineage and by analyzing a mouse mutant in which immunoglobulin lambda-chain-positive B cells are generated in the absence of rearrangements in the locus encoding immunoglobulin kappa-chain, we define h...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.1732
更新日期:2009-06-01 00:00:00
abstract::All complexes of T cell receptors (TCRs) bound to peptide-major histocompatibility complex (pMHC) molecules assume a stereotyped binding 'polarity', despite wide variations in TCR-pMHC docking angles. However, existing TCR-pMHC crystal structures have failed to show broadly conserved pairwise interaction motifs. Here ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1502
更新日期:2007-09-01 00:00:00
abstract::During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a speciali...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3543
更新日期:2016-10-01 00:00:00
abstract::Two potential outcomes confront proliferating antigen-stimulated naive T cells: differentiation to effector and memory cells, or deletion. How stimulation affects cell fate is unclear. Autonomous CD8+ T cell differentiation has been proposed, but this does not explain the abortive proliferation of T cells induced by i...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni908
更新日期:2003-04-01 00:00:00
abstract::Immunological reactions are propelled by ever-changing signals that alter the translational ability of the RNA in the cells involved. Such alterations are considered to be consequential modifications in the transcriptomic decoding of the genetic blueprint. The identification of RNA-binding protein (RBP) assemblies eng...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/ni.2884
更新日期:2014-06-01 00:00:00
abstract::B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylatio...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-018-0156-5
更新日期:2018-08-01 00:00:00
abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title:Nature immunology
pub_type: 已发布勘误
doi:10.1038/s41590-019-0476-0
更新日期:2019-10-01 00:00:00
abstract::Chemoattractant-stimulated granule release from neutrophils, basophils and eosinophils is critical for the innate immune response against infectious bacteria. Interleukin 8 (IL-8) activation of the chemokine receptor CXCRI was found to stimulate rapid formation of beta-arrestin complexes with Hck or c-Fgr. Formation o...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/79767
更新日期:2000-09-01 00:00:00
abstract::In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.2981
更新日期:2014-10-01 00:00:00
abstract::Plant proteins belonging to the nucleotide-binding site-leucine-rich repeat (NBS-LRR) family are used for pathogen detection. Like the mammalian Nod-LRR protein 'sensors' that detect intracellular conserved pathogen-associated molecular patterns, plant NBS-LRR proteins detect pathogen-associated proteins, most often t...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/ni1410
更新日期:2006-12-01 00:00:00
abstract::Mutational spectra analysis of 15 immunoglobulin genes suggested that consensus motifs RGYW and WA were universal descriptors of somatic hypermutation. Highly mutable sites, "hotspots", that matched WA were preferentially found in one DNA strand and RGYW hotspots were found in both strands. Analysis of base-substituti...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/88732
更新日期:2001-06-01 00:00:00
abstract::The glycolipid alpha-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic alpha-galactosylceramide at a resolution of 3.0 A. The structure shows a tightly fit lipid in the CD1d binding groove, with the sp...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1225
更新日期:2005-08-01 00:00:00
abstract::Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases. ...
journal_title:Nature immunology
pub_type:
doi:10.1038/ni0910-769
更新日期:2010-09-01 00:00:00
abstract::The activation of an immune response requires recognition of microorganisms by host receptors. In drosophila, detection of Gram-positive bacteria is mediated by cooperation between the peptidoglycan-recognition protein-SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) proteins. Here we show that some Gram-posit...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1123
更新日期:2004-11-01 00:00:00
abstract::Chemokines are chemoattractant proteins that are divided into subfamilies based upon cysteine signature motifs termed C, CC, CXC and CX3C. Chemokines have roles in immunity and inflammation that affect cell trafficking and activation of T cells as well as cells of the innate immune system. We report here CX3C chemokin...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/90675
更新日期:2001-08-01 00:00:00
abstract::During the productive interaction of T cells with antigen-presenting cells (APCs), engaged receptors, including the T cell antigen receptors and their associated tyrosine kinases, assemble into spatially segregated supramolecular activation clusters (SMACs) at the area of cell contact. Here, we studied intracellular s...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni836
更新日期:2002-10-01 00:00:00
abstract::Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in I...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.2187
更新日期:2011-11-20 00:00:00
abstract::CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue t...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-020-00850-9
更新日期:2021-01-11 00:00:00
abstract::Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 cells differentiated independently but shared overlapping effector function programs that were m...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3582
更新日期:2016-12-01 00:00:00