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 to induce CD8+ T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8+ T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Liu Y,Zhou N,Zhou L,Wang J,Zhou Y,Zhang T,Fang Y,Deng J,Gao Y,Liang X,Lv J,Wang Z,Xie J,Xue Y,Zhang H,Ma J,Tang K,Fang Y,Cheng F,Zhang C,Dong B,Zhao Y,Yuan P,Gao Q,Zhang H,Xiao-Feng Qin F,Huang Bdoi
10.1038/s41590-020-00850-9subject
Has Abstractpub_date
2021-01-11 00:00:00eissn
1529-2908issn
1529-2916pii
10.1038/s41590-020-00850-9pub_type
杂志文章abstract::Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of ...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/s41590-017-0022-x
更新日期:2018-02-01 00:00:00
abstract::Autophagy is an intracellular bulk degradation system that is highly conserved in eukaryotes. The discovery of autophagy-related ('ATG') proteins in the 1990s greatly advanced the mechanistic understanding of autophagy and clarified the fact that autophagy serves important roles in various biological processes. In add...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/ni.3273
更新日期:2015-10-01 00:00:00
abstract::Hematopoiesis requires tight regulation of the hematopoietic stem cell (HSC) population; however, the dynamics of HSC use at steady state are uncertain. Over 3-7 months, we evaluated the repopulation and self-renewal of more than 600 individual human 'severe combined immunodeficiency mouse-repopulating cells' (SRCs), ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1393
更新日期:2006-11-01 00:00:00
abstract::CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antib...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.2890
更新日期:2014-07-01 00:00:00
abstract::The transcription factor BATF directly regulates key components of the formation and function of follicular helper T cells and antibody class switching in B cells. ...
journal_title:Nature immunology
pub_type: 评论,新闻
doi:10.1038/ni.2042
更新日期:2011-06-01 00:00:00
abstract::T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1321
更新日期:2006-05-01 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::Chemokines facilitate leukocyte migration and positioning as well as other processes such as angiogenesis and leukocyte degranulation. The burgeoning knowledge on chemokines and their receptors has influenced many aspects of immunology, in part because cell migration is intimately related to leukocyte function. This o...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/84298
更新日期:2001-02-01 00:00:00
abstract::In the steady state, dendritic cells (DCs) in the lymph node induce T cell tolerance to self antigens. Innate signals trigger the maturation of tissue DCs, which migrate into lymph nodes and activate T cells. To examine DCs in vivo, we produced transgenic mice whose DCs expressed enhanced yellow fluorescent protein. T...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1139
更新日期:2004-12-01 00:00:00
abstract:: ...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-018-0147-6
更新日期:2018-07-01 00:00:00
abstract::Regulatory T cells (Treg cells) can express the transcription factors T-bet and GATA-3, but the function of this expression and whether such cells represent stable subsets is still unknown. By using various reporter tools, we found that the expression of T-bet and GATA-3 in Treg cells was dynamically influenced by the...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3053
更新日期:2015-02-01 00:00:00
abstract::Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-transl...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3487
更新日期:2016-08-01 00:00:00
abstract::The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cell...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3470
更新日期:2016-07-01 00:00:00
abstract::During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent repor...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3514
更新日期:2016-08-01 00:00:00
abstract::The present paradigm dictates that phagocytosis is accomplished mainly by 'professional' phagocytes (such as macrophages and monocytes), whereas B cells lack phagocytic capabilities. Here we demonstrate that B cells from teleost fish have potent in vitro and in vivo phagocytic activities. Particle uptake by B cells in...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1389
更新日期:2006-10-01 00:00:00
abstract::Activated T helper cells produce many cytokines, some of which are secreted through the immunological synapse toward the antigen-presenting cell. Here we have used immunocytochemistry, live-cell imaging and a surface-mediated secretion assay to show that there are two cytokine export pathways in T helper cells. Some c...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1304
更新日期:2006-03-01 00:00:00
abstract::The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly unders...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-019-0582-z
更新日期:2020-02-01 00:00:00
abstract::Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to a...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/s41590-019-0347-8
更新日期:2019-05-01 00:00:00
abstract::Cysteinyl leukotrienes are established mediators of bronchial asthma and have agonist roles analogous to those of histamine in allergic rhinitis. We now know that the substance originally termed slow-reacting substance of anaphylaxis was composed of three cysteinyl leukotrienes that act in the inflammatory response vi...
journal_title:Nature immunology
pub_type: 历史文章,杂志文章
doi:10.1038/ni0208-113
更新日期:2008-02-01 00:00:00
abstract::Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expressio...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3714
更新日期:2017-05-01 00:00:00
abstract::Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosyl...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1482
更新日期:2007-08-01 00:00:00
abstract::Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish ...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/ni1178
更新日期:2005-04-01 00:00:00
abstract::Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during ly...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.1695
更新日期:2009-02-01 00:00:00
abstract::Neutrophils encounter and 'prioritize' many chemoattractants in their pursuit of bacteria. Here we tested the possibility that the phosphatase PTEN is responsible for the prioritization of chemoattractants. Neutrophils induced chemotaxis by two separate pathways, the phosphatidylinositol-3-OH kinase (PI(3)K) phosphata...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.1623
更新日期:2008-07-01 00:00:00
abstract::The variable lymphocyte receptors (VLRs) of jawless vertebrates such as lamprey and hagfish are composed of highly diverse modular leucine-rich repeats. Each lymphocyte assembles a unique VLR by rearrangement of the germline gene. In the lamprey genome, we identify here about 850 distinct cassettes encoding leucine-ri...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1463
更新日期:2007-06-01 00:00:00
abstract::Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestra...
journal_title:Nature immunology
pub_type: 杂志文章,评审
doi:10.1038/ni.1937
更新日期:2010-10-01 00:00:00
abstract::Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intra...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.2573
更新日期:2013-06-01 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::Gadd45beta (growth arrest and DNA damage-inducible, beta) is involved in cell cycle arrest, apoptosis, signal transduction and cell survival. In T cells, Gadd45b was rapidly induced by T cell receptor (TCR) and inflammatory signals. Deficiency of Gadd45beta in CD4+ T cells impaired their responses to TCR stimulation o...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni1020
更新日期:2004-01-01 00:00:00
abstract::The transcription factor Aire controls immunological tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire's specificity, we performed single-cell RNA-seq and DNA-methylation analysis of Aire-suffi...
journal_title:Nature immunology
pub_type: 杂志文章
doi:10.1038/ni.3247
更新日期:2015-09-01 00:00:00