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Cited by 752T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment

Open access
Crespo, Joel, Sun, Haoyu, Welling, Theodore H, Tian, Zhigang, Zou, Weiping·2013·Current Opinion in Immunology
DOI 10.1016/j.coi.2012.12.003PMC PMC3636159
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Abstract

Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironments. We suggest that targeting T cell dysfunctional mechanisms and introducing/promoting T cell stemness are important approaches to treat patients with cancer.

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Crossref · 10.1016/j.coi.2012.12.003

Cites

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Claims the paper makes

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  • Premisecitation

    There is evidence of antigen-specific, T cell-intrinsic dysfunction in the tumor microenvironment.

    “There is evidence indicating antigen specific, T cell-intrinsic dysfunction in the tumor microenvironment [15,16].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Nazareth MR Broderick L Simpson-Abelson MR Kelleher RJ Jr Yokota SJ Bankert RB Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells J Immunol 2007 178 5552 5562 17442937 source

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    • cites [16] Broderick L Brooks SP Takita H Baer AN Bernstein JM Bankert RB IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells Clin Immunol 2006 118 159 169 16271513 source

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  • Interpretationreasoning

    The B7 family imbalance creates a poor co-stimulatory, high co-inhibitory environment that promotes T cell anergy.

    “This indicates a poor co-stimulatory, high co-inhibitory and therefore anergy-promoting environment.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    T cell exhaustion may be a layered or progressive process resulting from repeated activation.

    “T cell exhaustion may be a layered or progressive process to which T cells fall upon repeated activation.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    In persistent disease settings such as chronic infection and malignancies, T cells acquire multiple inhibitory surface molecules that effectively prevent T cell activation.

    “T cells acquiring multiple inhibitory surface molecules in persistent disease settings such as chronic infection [37,38] and malignancies [30,**39,40], which effectively prevent T cell activation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Wherry EJ Ha SJ Kaech SM Haining WN Sarkar S Kalia V Subramaniam S Blattman JN Barber DL Ahmed R Molecular signature of CD8+ T cell exhaustion during chronic viral infection Immunity 2007 27 670 684 17950003 source

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    • cites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source

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    • cites [30,**39,40]

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  • Interpretationnone given

    Tumor-induced T cell anergy may be one of the immune evasion mechanisms in patients with cancer.

    “In summary, tumor induced T cell anergy may be one of the immune evasion mechanisms in patients with cancer.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    In mouse studies, B7-H1/PD-1 signaling was proposed to mediate CD8+ T cell functional exhaustion in chronic infection, and PD-1 was proposed as a marker for exhausted T cells.

    “Initial mouse studies have proposed that B7-H1/PD-1 signaling pathway mediates CD8+ T cell functional exhaustion in the context of chronic infection, and PD-1 was proposed to be a marker for exhausted T cells [*29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [*29]

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    Premisecitation

    Activated T cells and early-stage effector T cells may express PD-1 and remain functional.

    “Notably, activated T cells and effector T cells in the early stage may express PD-1 and remain functional [35,*36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35,*36]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The anergy program is initiated by improper mTOR and Ras/MAPK signaling downstream of TCR/CD28 engagement.

    “It has been suggested that the anergy program is initiated by improper mTOR and Ras/MAPK signaling in the cell, a pathway which lies directly downstream of TCR/CD28 engagement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [**19,20]

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  • May combine two claims.

    Premisecitation

    In animal models, introducing B7-1 into tumors or blocking inhibitory B7 family members reduces tumor growth or causes spontaneous tumor rejection.

    “Animal model studies have shown that introduction of B7-1 into tumors by transfection or blockade of inhibitory B7 family members can reduce tumor growth or result in spontaneous tumor rejection in vivo [7–13].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [7] Zou W Chen L Inhibitory B7-family molecules in the tumour microenvironment Nat Rev Immunol 2008 8 467 477 18500231 source

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    • cites [8] Blank C Brown I Peterson AC Spiotto M Iwai Y Honjo T Gajewski TF PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells Cancer Res 2004 64 1140 1145 14871849 source

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    • cites [9] source

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    • cites [10] Kryczek I Zou L Rodriguez P Zhu G Wei S Mottram P Brumlik M Cheng P Curiel T Myers L B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma J Exp Med 2006 203 871 881 16606666 PMC2118300 source

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    • cites [11] Chen L Ashe S Brady WA Hellstrom I Hellstrom KE Ledbetter JA McGowan P Linsley PS Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4 Cell 1992 71 1093 1102 1335364 source

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    • cites [12] Gajewski TF B7-1 but not B7-2 efficiently costimulates CD8+ T lymphocytes in the P815 tumor system in vitro J Immunol 1996 156 465 472 8543795 source

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    • cites [13] Blank C Kuball J Voelkl S Wiendl H Becker B Walter B Majdic O Gajewski TF Theobald M Andreesen R Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro Int J Cancer 2006 119 317 327 16482562 source

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  • May combine two claims.

    Premisecitation

    Human tumor cells and/or tumor-associated APCs express B7-H1, and the B7-H1/PD-1 pathway mediates immune suppression.

    “it was demonstrated that human tumor cells and/or tumor associated APCs expressed B7-H1, and B7-H1/PD-1 pathway mediated immune suppression [**9]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [**9]

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    Premisecitation

    Tim-3, LAG-3, and BTLA are co-expressed with PD-1, and this co-expression strongly correlates with immune dysfunction in cancer patients.

    “In the course of defining exhausted PD-1+ T cells, T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) [39,41], lymphocyte-activation gene (LAG)-3 [38], and the B and T-cell lymphocyte attenuator (BTLA, CD272) [42,43] were found to be co-expressed with PD-1, and the co-expression has been strongly correlated with immune dysfunction in patients with cancer.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [39] source

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    • cites [41] Zhou Q Munger ME Veenstra RG Weigel BJ Hirashima M Munn DH Murphy WJ Azuma M Anderson AC Kuchroo VK Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia Blood 2011 117 4501 4510 21385853 PMC3099570 source

      Not checked in the free run.

    • cites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source

      Not checked in the free run.

    • cites [42] Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C Kirkwood JM Olive D Kuchroo V Zarour HM CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer Res 2012 72 887 896 22205715 PMC3288235 source

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    • cites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The E3 ubiquitin ligase family can affect PI3K, mTOR, and Ras/MAPK signaling and helps actively maintain anergy.

    “The E3 ubiquiting ligase family can affect PI3K, mTOR, and Ras/MAPK signaling pathways and help to actively maintain anergy [21,23,24].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Anandasabapathy N Ford GS Bloom D Holness C Paragas V Seroogy C Skrenta H Hollenhorst M Fathman CG Soares L GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells Immunity 2003 18 535 547 12705856 source

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    • cites [23] Jeon MS Atfield A Venuprasad K Krawczyk C Sarao R Elly C Yang C Arya S Bachmaier K Su L Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction Immunity 2004 21 167 177 15308098 source

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    • cites [24] Mueller DL E3 ubiquitin ligases as T cell anergy factors Nat Immunol 2004 5 883 890 15334084 source

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  • May combine two claims.

    Premisecitation

    In a lymphopenic host, homeostatic proliferation of anti-tumor T cells reverses anergy and promotes tumor rejection in vivo.

    “Homeostatic proliferation of anti-tumor T cells in a lymphopenic host both reverses anergy and promotes tumor rejection in vivo [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Brown IE Blank C Kline J Kacha AK Gajewski TF Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection J Immunol 2006 177 4521 4529 16982889 source

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The genetic reprogramming effects of the Ca2+ imbalance are hypothesized to be mediated by NFAT homodimer formation and transcription of anergy-inducing genes.

    “The effects of this imbalance on the genetic reprogramming of these cells have been hypothesized to be mediated by NFAT homodimer formation and transcription of anergy-inducing genes [21,22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Anandasabapathy N Ford GS Bloom D Holness C Paragas V Seroogy C Skrenta H Hollenhorst M Fathman CG Soares L GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells Immunity 2003 18 535 547 12705856 source

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    • cites [22] Soto-Nieves N Puga I Abe BT Bandyopadhyay S Baine I Rao A Macian F Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance J Exp Med 2009 206 867 876 19307325 PMC2715123 source

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  • May combine two claims.

    Premisecitation

    HCC-associated Tim-3+ T cells express reduced CD28, suggesting they may be at an early senescence stage.

    “HCC-associated Tim-3+T cells expressed reduced CD28, suggesting that these cells may be early senescence stage [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source

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  • May combine two claims.

    Premisecitation

    Human tumor-associated Th17 cells express stem cell markers and exhibit stem cell-like features.

    “In line with these limited reports in non-tumor system, human tumor associated Th17 cells expressed stem cell markers and exhibited stem cell like features.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [**71,**72]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cell cycle controlling proteins p16, p21, and p53 normally inhibit cell cycle progression and accumulate in senescent cells.

    “Cell cycle controlling proteins p16, p21, and p53, normally inhibit cell cycle progression and have been shown to be accumulated in senescent cells [49–51].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [49] Passos JF Nelson G Wang C Richter T Simillion C Proctor CJ Miwa S Olijslagers S Hallinan J Wipat A Feedback between p21 and reactive oxygen production is necessary for cell senescence Mol Syst Biol 2010 6 347 20160708 PMC2835567 source

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    • cites [50] Rodier F Coppe JP Patil CK Hoeijmakers WA Munoz DP Raza SR Freund A Campeau E Davalos AR Campisi J Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion Nat Cell Biol 2009 11 973 979 19597488 PMC2743561 source

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    • cites [51] Beausejour CM Krtolica A Galimi F Narita M Lowe SW Yaswen P Campisi J Reversal of human cellular senescence: roles of the p53 and p16 pathways EMBO J 2003 22 4212 4222 12912919 PMC175806 source

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    Premisecitation

    Telomere shortening is an inherent byproduct of cell division that affects cellular function and leads to cell senescence.

    “Telomere shortening is an inherent byproduct of cellular division, which affects cellular function and leads to cell senescence [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Hayflick L Moorhead PS The serial cultivation of human diploid cell strains Exp Cell Res 1961 25 585 621 13905658 source

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  • May combine two claims.

    Premisecitation

    Mouse central memory T cells are arrested at a pre-differentiation stage by transcriptional inhibitors and retain replicative potential and long-term production of effector T cells after a second antigen challenge.

    “The concept of T cell stemness was initially stemmed from the observations that mouse central memory T cells are arrested at a pre-differentiation stage by transcriptional inhibitors and retain replicative potential and long-term production of effector T cells after a second antigen challenge [67].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Fearon DT Manders P Wagner SD Arrested differentiation, the self-renewing memory lymphocyte, and vaccination Science 2001 293 248 250 11452114 source

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  • May combine two claims.

    Premisecitation

    Bat3 localization at the Tim-3 cytoplasmic tail allows continued T cell proliferation and IFNγ production, an effect lost in Bat3-deficient cells and upon Tim-3 binding to galectin-9.

    “Bat3 localization at this protein region allows T cells continued proliferation and IFNγ production, an effect that was lost on Bat3 deficient cells and upon Tim-3 binding to galectin-9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Rangachari M Zhu C Sakuishi K Xiao S Karman J Chen A Angin M Wakeham A Greenfield EA Sobel RA Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion Nat Med 2012 18 1394 1400 22863785 PMC3491118 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T cells co-expressing these surface molecules show significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.

    “In these studies, T cells co-expressing these surface molecules show a significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [39] source

      Not checked in the free run.

    • cites [41] Zhou Q Munger ME Veenstra RG Weigel BJ Hirashima M Munn DH Murphy WJ Azuma M Anderson AC Kuchroo VK Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia Blood 2011 117 4501 4510 21385853 PMC3099570 source

      Not checked in the free run.

    • cites [38] Blackburn SD Shin H Haining WN Zou T Workman CJ Polley A Betts MR Freeman GJ Vignali DA Wherry EJ Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection Nat Immunol 2009 10 29 37 19043418 PMC2605166 source

      Not checked in the free run.

    • cites [42] Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C Kirkwood JM Olive D Kuchroo V Zarour HM CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer Res 2012 72 887 896 22205715 PMC3288235 source

      Not checked in the free run.

    • cites [43] Derre L Rivals JP Jandus C Pastor S Rimoldi D Romero P Michielin O Olive D Speiser DE BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination J Clin Invest 2010 120 157 167 20038811 PMC2799219 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cancer-associated Tim-3+ T cells may contain senescent cells and experience cell cycle arrest in G1/S phase.

    “It suggests that cancer associated Tim-3+ T cells may contain senescent cells and experience cell cycle arrest in G1/S phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senescent T cells have defective killing abilities and develop negative regulatory functions.

    “In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Appay V Nixon DF Donahoe SM Gillespie GM Dong T King A Ogg GS Spiegel HM Conlon C Spina CA HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function J Exp Med 2000 192 63 75 10880527 PMC1887711 source

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    • cites [53] Akbar AN Henson SM Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 2011 11 289 295 21436838 source

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  • May combine two claims.

    Premisecitation

    Clinical blockade of B7-H1/PD-1 may rescue T cell effector functions in vivo and results in significant objective clinical responses.

    “A promising aspect is that clinical blockade of B7-H1/PD-1, the key T cell exhaustion pathway, may rescue T cell effector functions in vivo, and results in significant objective clinical responses [32,33].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] source

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    • cites [33] source

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  • May combine two claims.

    Premisecitation

    Human HCC-associated T cells highly express Tim-3 and cyclin-dependent kinase inhibitors, interact with galectin-9+ myeloid APCs, and fail to enter the cell cycle.

    “human HCC- associated T cells highly express Tim-3 and cyclin dependent kinase inhibitors, and interact with galectin-9+myeloid APCs. These cells fail to enter the cell cycle [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Li H Wu K Tao K Chen L Zheng Q Lu X Liu J Shi L Liu C Wang G Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma Hepatology 2012 56 1342 1351 22505239 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bat3 modulates Tim-3 function on T cells by interacting with the Tim-3 cytoplasmic tail.

    “it has been postulated that the human leukocyte antigen (HLA)-B-associated transcript 3 (Bat3) modulates Tim-3 function on T cells by interacting with Tim-3 cytoplasmic tail [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Rangachari M Zhu C Sakuishi K Xiao S Karman J Chen A Angin M Wakeham A Greenfield EA Sobel RA Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion Nat Med 2012 18 1394 1400 22863785 PMC3491118 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent T cells are characterized by telomere shortening, loss of CD28 expression, and cell cycle arrest.

    “Senescent T cells are characterized by telomere shortenings, phenotypic change (loss of CD28 expression), and cell cycle arrest [46,47] (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Adibzadeh M Pohla H Rehbein A Pawelec G Long-term culture of monoclonal human T lymphocytes: models for immunosenescence? Mech Ageing Dev 1995 83 171 183 8583835 source

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    • cites [47] Effros RB Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly Am J Hum Genet 1998 62 1003 1007 9545415 PMC1377102 source

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  • May combine two claims.

    Premisecitation

    Senescent CD28−/dim CD8+ T cells are observed in patients with lung cancer and head and neck cancer.

    “Phenotypically, senescent CD28−/dimCD8+T cells are observed in patients with lung cancers [57], head and neck cancer [58].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Meloni F Morosini M Solari N Passadore I Nascimbene C Novo M Ferrari M Cosentino M Marino F Pozzi E Foxp3 expressing CD4+ CD25+ and CD8+CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma Hum Immunol 2006 67 1 12 16698419 source

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    • cites [58] Tsukishiro T Donnenberg AD Whiteside TL Rapid turnover of the CD8(+)CD28(−) T-cell subset of effector cells in the circulation of patients with head and neck cancer Cancer Immunol Immunother 2003 52 599 607 12827303 PMC11032778 source

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  • May combine two claims.

    Premisecitation

    In a mouse model, CD44lowCD62Lhigh memory CD8+ T cells express high levels of Sca-1, Bcl-2, and CD122, and because they show robust self-renewal and multipotent capacity to generate central and effector memory T cells, they were designated T memory stem cells.

    “In a mouse model, CD44lowCD62Lhigh memory CD8+ T cells express high levels of stem cell antigen-1 (Sca-1), Bcl-2 and common IL-2 and IL-15 receptor β chain (CD122). Because these cells showed robust self-renewal and the multipotent capacity to generate central memory and effector memory T cells, they were designated T memory stem cells [69].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Zhang Y Joe G Hexner E Zhu J Emerson SG Host-reactive CD8+ memory stem cells in graft-versus-host disease Nat Med 2005 11 1299 1305 16288282 source

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  • May combine two claims.

    Interpretationcitation

    Cells in younger patients may become senescent, and chronic activation and proliferation may cause T cell senescence.

    “This suggests that cells in younger patients may become senescent, and chronic activation and proliferation may still cause T cell senescence [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Vallejo AN Weyand CM Goronzy JJ T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection Trends Mol Med 2004 10 119 124 15102354 source

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  • May combine two claims.

    Premisecitation

    Galectin-9 induces intracellular calcium flux, aggregation, and death of Th1 cells in a Tim-3-dependent manner.

    “Galectin-9 induces intracellular calcium flux, aggregation and death of Th1 cells in Tim-3-dependent manner [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Zhu C Anderson AC Schubart A Xiong H Imitola J Khoury SJ Zheng XX Strom TB Kuchroo VK The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity Nat Immunol 2005 6 1245 1252 16286920 source

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  • May combine two claims.

    Interpretationcitation

    PD-1 may mark exhausted cells, Tim-3 and KLRG-1 may mark senescent cells, and mouse stem-like T cells may express Sca-1.

    “It is arguable but experimentally operative that PD-1 may be a marker for exhausted cells, Tim-3 and KLRG-1 may be markers for senescent cells, and mouse stem-like T cells may express Sca-1 [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Gattinoni L Zhong XS Palmer DC Ji Y Hinrichs CS Yu Z Wrzesinski C Boni A Cassard L Garvin LM Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells Nat Med 2009 15 808 813 19525962 PMC2707501 source

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  • May combine two claims.

    Interpretationreasoning

    B7-H1/PD-1 and Tim-3/galectin-9 signaling pathways may synergistically and/or additively mediate T cell dysfunction, and simultaneous blockade may improve T cell immunity.

    “it is evident that B7-H1/PD-1 and Tim-3/galectin-9 signaling pathways may synergistically and/or additively mediate T cell dysfunction, and simultaneous blockade of these pathways may result in improved T cell immunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Human Th17 cells give rise to distinct Th lineages, as measured by IFNγ and Foxp3+ cell expression, and have heightened self-renewal and survival capabilities.

    “Human Th17 cells were shown to give rise to distinct Th lineages, as measured through the expression of IFNγ, and Foxp3+ cells, heightened self-renewal, and survival capabilities [71,72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] source

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    • cites [72] source

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    Premisecitation

    Th17 cells retain a stem cell-like phenotype through coordinated effects of HIF1α/Notch/Bcl-2 and are potent anti-tumor effectors.

    “Interestingly, Th17 cells retain a stem cell-like phenotype through the coordinated effects of HIF1α/Notch/Bcl-2 and are also potent anti-tumor effectors [71], suggesting that stemness might correlate with better immune responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] source

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  • May combine two claims.

    Interpretationcitation

    Human Th17 cells have stem cell properties at genetic, molecular, and functional levels and are long-lived.

    “Human Th17 cells have certain “stem cell properties” at the genetic, molecular and functional levels, and are long-lived cells.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Mouse and human Th17 cells display greater survival potential, persistence, and the ability to repopulate sub-lethally irradiated mice.

    “When measured for their biological activity, mouse and human Th17 cells displayed greater survival potential, persistence as well as the ability of repopulating sub-lethally irradiated mice [**71,**72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [**71,**72]

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32 of 32

  • The paper relies on this without support.

    Human tumors progress despite the presence of tumor-associated antigen-specific T cells.

    “Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells.”

  • The paper relies on this without support.

    T cell exhaustion occurs when T cells are chronically activated at sites of chronic inflammation, such as cancer, autoimmunity, and chronic infection.

    “T cell exhaustion occurs when T cells are chronically activated at sites of chronic inflammation, such as cancer, autoimmunity, and chronic infection.”

  • The authors state this as an assumption.

    The tumor microenvironment provides the necessary conditions for effector T cells to become functionally exhausted and to maintain this state during disease progression.

    “Nonetheless, it is assumed that the tumor microenvironment provides the necessary conditions for effector T cells to become functionally exhausted as well as being able to maintain this state during disease progression.”

  • The paper relies on this without support.

    These markers are not mutually exclusive or inclusive in a given T cell subset.

    “However, these markers are not mutually exclusive and inclusive in a given T cell subset.”

  • The paper relies on this without support.

    PD-1+ cells may express Tim-3 and LAG-3.

    “PD-1+ cells may express Tim-3 and LAG-3.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Exhausted T cells are usually CM/EM T cells that have been chronically stimulated.

    “Exhausted T cells are usually CM/EM T cells that have been chronically stimulated [341].”

    From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [341]

    The “T cell exhaustion” section says exhaustion occurs when T cells are chronically activated and describes exhausted cells as effector T cells. It does not say they are usually central-memory or effector-memory (CM/EM) T cells; those memory subsets are discussed separately in “T cell stemness.” Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • During aging, the cytotoxic activity of immune cells decreases, and the expression of functional molecules associated with cytotoxic activity, such as IFN-γ, granzyme B, and perforin, is reduced.

    “More recent studies have shown that, during aging, the cytotoxic activity of immune cells decreases, and the expression of functional molecules associated with cytotoxic activity, such as interferon gamma (IFN-γ), granzyme B, and perforin, is also reduced [31–34] (Table 1).”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [31]

  • T cell senescence is irreversible, whereas anergy and exhaustion are considered reversible.

    “T cell senescence is irreversible, as opposed to their anergy and exhaustion, both of which are considered reversible [31, 38–40].”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [31]

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Authors
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W.
Affiliations
  • University of Michigan (US)
  • University of Science and Technology of China (CN)
Corresponding author
  • Tian, Zhigang
  • Zou, Weiping
ORCID
Venue
Current Opinion in Immunology
Publisher
Elsevier BV
Published
2013-04
Volume
25
Issue
2
Pages
214-221
ISSN
0952-7915 (ISSN-L)
DOI
10.1016/j.coi.2012.12.003
PMC
PMC3636159
OpenAlex
W2050558251
Cited by
752
References
77
Citations by year
2026: 32 · 2025: 67 · 2024: 74 · 2023: 76 · 2022: 73 · 2021: 80 · 2020: 63 · 2019: 59 · 2018: 61 · 2017: 52 · 2016: 42 · 2015: 42 · 2014: 23 · 2013: 8
FWCI
3.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5t32ai007413-32)
  • National Cancer Institute (R01CA123088, R01CA152470, R01CA156685, K08CA151414, R01CA099985)
  • National Institute of Allergy and Infectious Diseases (T32-AI-007413)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
T cell anergy, T cell exhaustion, T cell senescence, T cell stemness, tumor microenvironment, tumor-associated antigens, immune evasion, immunosuppression, cancer immunotherapy
MeSH terms
Animals, Humans, Neoplasms, Stem Cells, T-Lymphocytes, Cellular Senescence, Clonal Anergy, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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