IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor.

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 Immunol

journal_title

Nature immunology

authors

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 B

doi

10.1038/s41590-020-00850-9

subject

Has Abstract

pub_date

2021-01-11 00:00:00

eissn

1529-2908

issn

1529-2916

pii

10.1038/s41590-020-00850-9

pub_type

杂志文章
  • Myeloid-derived suppressor cells coming of age.

    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

    authors: Veglia F,Perego M,Gabrilovich D

    更新日期:2018-02-01 00:00:00

  • Autophagy and autophagy-related proteins in the immune system.

    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

    authors: Shibutani ST,Saitoh T,Nowag H,Münz C,Yoshimori T

    更新日期:2015-10-01 00:00:00

  • Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment.

    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

    authors: McKenzie JL,Gan OI,Doedens M,Wang JC,Dick JE

    更新日期:2006-11-01 00:00:00

  • The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.

    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

    authors: Wang H,Geng J,Wen X,Bi E,Kossenkov AV,Wolf AI,Tas J,Choi YS,Takata H,Day TJ,Chang LY,Sprout SL,Becker EK,Willen J,Tian L,Wang X,Xiao C,Jiang P,Crotty S,Victora GD,Showe LC,Tucker HO,Erikson J,Hu H

    更新日期:2014-07-01 00:00:00

  • A BATF-ling connection between B cells and follicular helper T cells.

    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

    authors: Ellyard JI,Vinuesa CG

    更新日期:2011-06-01 00:00:00

  • Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance.

    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

    authors: Kallies A,Hawkins ED,Belz GT,Metcalf D,Hommel M,Corcoran LM,Hodgkin PD,Nutt SL

    更新日期:2006-05-01 00:00:00

  • Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.

    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

    authors: Stanislawski T,Voss RH,Lotz C,Sadovnikova E,Willemsen RA,Kuball J,Ruppert T,Bolhuis RL,Melief CJ,Huber C,Stauss HJ,Theobald M

    更新日期:2001-10-01 00:00:00

  • Chemokines: immunology's high impact factors.

    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

    authors: Mackay CR

    更新日期:2001-02-01 00:00:00

  • Visualizing dendritic cell networks in vivo.

    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

    authors: Lindquist RL,Shakhar G,Dudziak D,Wardemann H,Eisenreich T,Dustin ML,Nussenzweig MC

    更新日期:2004-12-01 00:00:00

  • Fiber against flu.

    abstract:: ...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/s41590-018-0147-6

    authors: Visan I

    更新日期:2018-07-01 00:00:00

  • Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance.

    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

    authors: Yu F,Sharma S,Edwards J,Feigenbaum L,Zhu J

    更新日期:2015-02-01 00:00:00

  • Control of the innate immune response by the mevalonate pathway.

    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

    authors: Akula MK,Shi M,Jiang Z,Foster CE,Miao D,Li AS,Zhang X,Gavin RM,Forde SD,Germain G,Carpenter S,Rosadini CV,Gritsman K,Chae JJ,Hampton R,Silverman N,Gravallese EM,Kagan JC,Fitzgerald KA,Kastner DL,Golenbock DT,Ber

    更新日期:2016-08-01 00:00:00

  • CIS is a potent checkpoint in NK cell-mediated tumor immunity.

    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

    authors: Delconte RB,Kolesnik TB,Dagley LF,Rautela J,Shi W,Putz EM,Stannard K,Zhang JG,Teh C,Firth M,Ushiki T,Andoniou CE,Degli-Esposti MA,Sharp PP,Sanvitale CE,Infusini G,Liau NP,Linossi EM,Burns CJ,Carotta S,Gray DH,Se

    更新日期:2016-07-01 00:00:00

  • Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment.

    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

    authors: Kueh HY,Yui MA,Ng KK,Pease SS,Zhang JA,Damle SS,Freedman G,Siu S,Bernstein ID,Elowitz MB,Rothenberg EV

    更新日期:2016-08-01 00:00:00

  • B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities.

    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

    authors: Li J,Barreda DR,Zhang YA,Boshra H,Gelman AE,Lapatra S,Tort L,Sunyer JO

    更新日期:2006-10-01 00:00:00

  • T cells use two directionally distinct pathways for cytokine secretion.

    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

    authors: Huse M,Lillemeier BF,Kuhns MS,Chen DS,Davis MM

    更新日期:2006-03-01 00:00:00

  • Transcriptomic and epigenetic mechanisms underlying myeloid diversity in the lung.

    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

    authors: Sajti E,Link VM,Ouyang Z,Spann NJ,Westin E,Romanoski CE,Fonseca GJ,Prince LS,Glass CK

    更新日期:2020-02-01 00:00:00

  • Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

    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

    authors: Altman MC,Gill MA,Whalen E,Babineau DC,Shao B,Liu AH,Jepson B,Gruchalla RS,O'Connor GT,Pongracic JA,Kercsmar CM,Khurana Hershey GK,Zoratti EM,Johnson CC,Teach SJ,Kattan M,Bacharier LB,Beigelman A,Sigelman SM,Presnel

    更新日期:2019-05-01 00:00:00

  • The cysteinyl leukotrienes: where do they come from? What are they? Where are they going?

    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

    authors: Austen KF

    更新日期:2008-02-01 00:00:00

  • Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.

    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

    authors: Iwata A,Durai V,Tussiwand R,Briseño CG,Wu X,Grajales-Reyes GE,Egawa T,Murphy TL,Murphy KM

    更新日期:2017-05-01 00:00:00

  • Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death.

    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

    authors: Toscano MA,Bianco GA,Ilarregui JM,Croci DO,Correale J,Hernandez JD,Zwirner NW,Poirier F,Riley EM,Baum LG,Rabinovich GA

    更新日期:2007-08-01 00:00:00

  • Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

    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

    authors: Sakaguchi S

    更新日期:2005-04-01 00:00:00

  • Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

    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

    authors: Guimond M,Veenstra RG,Grindler DJ,Zhang H,Cui Y,Murphy RD,Kim SY,Na R,Hennighausen L,Kurtulus S,Erman B,Matzinger P,Merchant MS,Mackall CL

    更新日期:2009-02-01 00:00:00

  • PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils.

    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

    authors: Heit B,Robbins SM,Downey CM,Guan Z,Colarusso P,Miller BJ,Jirik FR,Kubes P

    更新日期:2008-07-01 00:00:00

  • Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase.

    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

    authors: Rogozin IB,Iyer LM,Liang L,Glazko GV,Liston VG,Pavlov YI,Aravind L,Pancer Z

    更新日期:2007-06-01 00:00:00

  • Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.

    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

    authors: Biswas SK,Mantovani A

    更新日期:2010-10-01 00:00:00

  • Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.

    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

    authors: Huang LR,Wohlleber D,Reisinger F,Jenne CN,Cheng RL,Abdullah Z,Schildberg FA,Odenthal M,Dienes HP,van Rooijen N,Schmitt E,Garbi N,Croft M,Kurts C,Kubes P,Protzer U,Heikenwalder M,Knolle PA

    更新日期:2013-06-01 00:00:00

  • AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch.

    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

    authors: Lee JS,Cella M,McDonald KG,Garlanda C,Kennedy GD,Nukaya M,Mantovani A,Kopan R,Bradfield CA,Newberry RD,Colonna M

    更新日期:2011-11-20 00:00:00

  • Gadd45beta is important for perpetuating cognate and inflammatory signals in T cells.

    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

    authors: Lu B,Ferrandino AF,Flavell RA

    更新日期:2004-01-01 00:00:00

  • Aire controls gene expression in the thymic epithelium with ordered stochasticity.

    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

    authors: Meredith M,Zemmour D,Mathis D,Benoist C

    更新日期:2015-09-01 00:00:00