Trends in Immunology
Volume 41, Issue 3, March 2020, Pages 200-212
Journal home page for Trends in Immunology

Opinion
T Cell Co-stimulation and Functional Modulation by Innate Signals

https://doi.org/10.1016/j.it.2020.01.003Get rights and content

Highlights

  • Some TLR ligands for TLR2/3/5/7/9 mediate co-stimulation of T cells with TCR triggering to induce cell proliferation and cytokine production.

  • TLR2 particularly mediates co-stimulation promoting differentiation of T helper (Th)1, Th9, and Th17 cells and directly stimulates the effector functions of mouse Th1, Th17, and CD8+ T cells.

  • Nucleic acid (NA) can induce co-stimulation of T cells, leading to Th2 cell differentiation.

  • Co-stimulation of T cells with STING ligands induces cell growth inhibition by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signals and simultaneously stimulates type I IFN responses through the sustained activation of interferon regulatory factor 3 (IRF3) and TCR-induced mTORC1 activation in mice.

Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs), play a pivotal role in the initiation of innate immune responses. Certain PRRs are also expressed by CD4+ and CD8+ T cells, where they function to provide co-stimulatory signals for their activation and differentiation. Recently, stimulator of interferon genes (STING) was found to be highly expressed in CD4+ and CD8+ T cells and to modulate T cell function. STING signaling inhibits cell growth and stimulates type I interferon (IFN-I) responses in T cells through reciprocal regulation between T cell receptor (TCR) and STING signals. Here, we propose a model whereby innate signals by TLRs and STING regulate TCR signals and T cell functions.

Section snippets

Expression and Signaling of Innate Receptors in T Cells

T cells are activated upon T cell receptor (TCR) recognition of antigen peptide-MHC, leading them to proliferate and differentiate into effector cells in the milieu of environmental factors. In addition to TCR signals, activation of T cells is positively and negatively controlled by several different signals through co-stimulatory receptors. The most critical positive co-stimulatory signal is provided by CD28 upon interaction with its ligands CD80/86 on antigen-presenting cells (APCs) [1]. By

Co-stimulation of T Cells by TLR Signals

TLRs are a class of innate immune system sensors that recognize pathogen-associated molecular patterns (PAMPs) (see Glossary) and damage-associated molecular patterns (DAMPs). They are expressed by innate immune cells such as dendritic cells (DCs) and macrophages (Mϕs), and activation of APCs by TLRs induces T cell activation through upregulation of MHC and co-stimulatory molecules and also promotes differentiation of effector CD4+ and CD8+ T cells by cytokine production [1]. TLR-induced

Regulation of T Cell Differentiation by Nucleic Acid (NA)-Mediated Co-stimulation

NA-sensing TLRs such as TLR3, TLR7/8, and TLR9 are predominantly expressed intracellularly in endosomal compartments in innate immune cells, allowing specific recognition of endocytosed pathogens [30]. TLR3, TLR7/8, and TLR9 sense double-stranded RNA, singe-stranded RNA, and unmethylated CpG motifs of DNA, respectively [30]. TLR3 ligands such as RNAs and TLR9 ligands such as DNA, directly enhance IL-2 production and proliferation of mouse and human naïve CD4+ and CD8+ T cells in vitro; together

The STING Signal Modulates Both Canonical IFN-I Responses and Growth Inhibition

STING is a PRR localized in the endoplasmic reticulum (ER) membrane [38] in innate immune cells and plays a central role in sensing cytosolic DNA upon infection with DNA viruses and retroviruses [38,39] (Box 2).

Based on earlier studies, STING had been thought to function exclusively in innate immune cells. However, mouse CD4+ T cells were recently shown to express even higher amounts of STING protein than innate immune cells such as Mϕs and DCs [17., 18., 19.]. However, the effect of STING

Reciprocal Regulation of STING and TCR Signaling

The nutrient-sensing kinase mTOR is activated by TCR/CD28 stimulation and environmental stimuli, regulates cellular metabolism and protein synthesis through downstream pathways such as 4E-BP1 and S6 kinase (S6K), and integrates these signals to regulate T cell function [47]. mTOR signals through two distinct complexes: mTORC1 and mTORC2, which contain the scaffold proteins Raptor and Rictor, respectively. T cell-specific gene deletion analyses have revealed that mTORC1 plays a critical role in

Physiological Impact of STING Signaling in T Cells

Accumulating evidence has shown critical roles of the STING pathway in antitumor immune responses in vivo. For example, the STING pathway has been deemed critical for achieving antitumor responses using radiation and immune checkpoint blockade therapies (e.g., PD-1/PD-L1 and CTLA4) in mice using several tumor model systems [53., 54., 55., 56.]. For example, intratumor administration of STING ligands alone in mice inhibited tumor growth (MC38 colon adenocarcinoma and B16 melanoma) and

Concluding Remarks

PRRs in innate immune cells trigger cell activation upon recognition of their ligands to induce inflammatory cytokine/chemokine production and upregulation of MHC and co-stimulatory molecules. By contrast, PRRs in naïve CD4+ and CD8+ T cells can serve as co-stimulatory receptors and modulate T cell functions, but only in conjunction with TCR stimulation. Whereas TLR2 and unknown NA sensors in CD4+ T cells may function as positive co-stimulatory molecules, STING in CD4+ T cells can function as a

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHI (grants 16K08852 for T.I. and 18H02672 and 17K19576 for T.S.).

Glossary

Aicardi-Goutieres syndrome
genetically based autoimmune disease characterized by DNA-triggered type I interferonopathy.
Autophagy
recycling process in which the cell degrades damaged, redundant, or dangerous cellular organelles and proteins in lysosomes.
Chimeric antigen receptor (CAR) targeted to CD19
recombinant chimeric receptors that combine antigen-binding and T cell activation function in a single receptor. CD19-CAR recognizes CD19 on tumors and exhibits cytotoxicity against tumor in a non-MHC

References (83)

  • R. Medzhitov

    Toll-like receptors and innate immunity

    Nat. Rev. Immunol.

    (2001)
  • L. Chen et al.

    Molecular mechanisms of T cell co-stimulation and co-inhibition

    Nat. Rev. Immunol.

    (2013)
  • M. Komai-Koma

    TLR2 is expressed on activated T cells as a costimulatory receptor

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • G. Caron

    Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells

    J. Immunol.

    (2005)
  • A. Cottalorda

    TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation

    Eur. J. Immunol.

    (2006)
  • R. Simone

    Stimulation of human CD4(+) T lymphocytes via TLR3, TLR5 and TLR7/8 up-regulates expression of costimulatory and modulates proliferation

    Open Microbiol. J.

    (2009)
  • A. Landrigan

    CpG and non-CpG oligodeoxynucleotides directly costimulate mouse and human CD4+ T cells through a TLR9- and MyD88-independent mechanism

    J. Immunol.

    (2011)
  • T. Meyer

    Poly(I:C) costimulation induces a stronger antiviral chemokine and granzyme B release in human CD4 T cells than CD28 costimulation

    J. Leukoc. Biol.

    (2012)
  • T. Imanishi

    Cutting edge: TLR2 directly triggers Th1 effector functions

    J. Immunol.

    (2007)
  • J.M. Reynolds

    Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease

    Immunity

    (2010)
  • A.F. Karim

    Toll like receptor 2 engagement on CD4(+) T cells promotes TH9 differentiation and function

    Eur. J. Immunol.

    (2017)
  • T. Imanishi

    Nucleic acid sensing by T cells initiates Th2 cell differentiation

    Nat. Commun.

    (2014)
  • M. Bruchard

    The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

    Nat. Immunol.

    (2015)
  • G. Arbore

    T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4(+) T cells

    Science

    (2016)
  • B.N. Martin

    T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis

    Nat. Immunol.

    (2016)
  • S. Cerboni

    Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes

    J. Exp. Med.

    (2017)
  • B. Larkin

    Cutting edge: activation of STING in T cells induces type I IFN responses and cell death

    J. Immunol.

    (2017)
  • M.F. Gulen

    Signalling strength determines proapoptotic functions of STING

    Nat. Commun.

    (2017)
  • T. Imanishi

    Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

    Life Sci. Alliance

    (2019)
  • K. Takeda

    Toll-like receptors

    Annu. Rev. Immunol.

    (2003)
  • G. Chen

    NOD-like receptors: role in innate immunity and inflammatory disease

    Annu. Rev. Pathol.

    (2009)
  • Y.M. Loo et al.

    Immune signaling by RIG-I-like receptors

    Immunity

    (2011)
  • O. Acuto et al.

    CD28-mediated co-stimulation: a quantitative support for TCR signalling

    Nat. Rev. Immunol.

    (2003)
  • S.B. Chodisetti

    Triggering through Toll-like receptor 2 limits chronically stimulated T-helper type 1 cells from undergoing exhaustion

    J. Infect. Dis.

    (2015)
  • S.L. Topalian

    Immune checkpoint blockade: a common denominator approach to cancer therapy

    Cancer Cell

    (2015)
  • W. Zou

    PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations

    Sci. Transl. Med.

    (2016)
  • N. Asprodites

    Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity

    FASEB J.

    (2008)
  • D. Geng

    When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function

    Blood

    (2010)
  • M. Quigley

    A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection

    Blood

    (2009)
  • K. Takeda et al.

    Toll-like receptors in innate immunity

    Int. Immunol.

    (2005)
  • J. Tabiasco

    Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor

    J. Immunol.

    (2006)
  • A.E. Gelman

    The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation

    Immunity

    (2006)
  • T. Marichal

    DNA released from dying host cells mediates aluminum adjuvant activity

    Nat. Med.

    (2011)
  • M. Kool

    An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma

    Immunity

    (2011)
  • C. Schorn

    Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells

    Front. Immunol.

    (2012)
  • I.J. Juncadella

    Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation

    Nature

    (2013)
  • M. Toussaint

    Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation

    Nat. Med.

    (2017)
  • H. Ishikawa et al.

    STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

    Nature

    (2008)
  • H. Ishikawa

    STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

    Nature

    (2009)
  • Z.J. Roberts

    The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis

    J. Exp. Med.

    (2007)
  • T. Cavlar

    Species-specific detection of the antiviral small-molecule compound CMA by STING

    EMBO J.

    (2013)
  • Cited by (0)

    View full text