Trends in Immunology
OpinionT Cell Co-stimulation and Functional Modulation by Innate Signals
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
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