Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Feb;39(2):112-122.
doi: 10.1016/j.it.2017.10.001. Epub 2017 Oct 20.

Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours

Francesca Levi-Schaffer  1 , Ofer Mandelboim  2
Affiliations
Review

Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours

Francesca Levi-Schaffer et al. Trends Immunol. 2018 Feb.

Abstract

Coactivating and inhibitory receptors that share at least one ligand interact with a wide variety of ligands, indicating their importance in a range of situations. Here, we discuss principles of mainly human paired receptor function and ligand recognition, and possible therapeutic implications of targeting these receptors in cancer, autoimmune diseases, and allergy. We summarise and emphasise the idea that these receptors, which have evolved in part in response to pathogen pressure, fine-tune the immune response, preserve homeostasis, and that pathogens and tumours use the dominance of the inhibitory receptors over the coactivating receptors to avoid immune elimination. Finally, we discuss the options of using paired receptors and their ligand for immune cell education and therapy.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Paired Receptors Mediate a Balanced Form of Inhibition. (A) Schematic representation of a receptor pair. The shared ligand can bind either receptor, but the receptors themselves have opposite downstream signals, either activating or inhibitory. (B) Several mechanisms cause the inhibitory signal to be dominant over the activating signal when both paired receptors are expressed on the same cell. (B1). The inhibitory receptor (marked in red), has a higher affinity for the shared ligand than the activating receptor in all receptor pairs (for example, TIGIT versus DNAM1 8, 38). (B2) As a result of its higher affinity for ligand, the inhibitory receptor competes with its activating partner for ligand binding such that the inhibitory receptor physically interrupts the binding of the activating receptor to the ligand , . (B3) There is also evidence that inhibitory receptors can interfere with the homodimerization of their corresponding activating receptor, thereby preventing signalling through the activating receptor (e.g., TIGIT can interfere with the homodimerisation of DNAM1 [20]). Abbreviations: DNAM1, DNAX accessory molecule 1; TIGIT, T cell immunoreceptor with immunglobulin and ITIM domains.
Figure 2
Figure 2
Using a Shared Ligand as a Cellular Entry Receptor Is Advantageous for Pathogens. (A) Evolutionary pressure favours viruses that use the shared ligands of paired receptors as entry and/or adhesion receptors. Host cells that express a shared ligand (shown in purple) are relatively protected from immune system attack because the shared ligand sends a dominant inhibitory signal to immune cells expressing the paired inhibitory (marked in red) and coactivating (marked in black) receptors. Therefore, viruses that enter and reproduce in cells expressing a shared ligand can avoid an immune response. Virus-infected host cells that do not express a shared ligand can be killed by the immune system. (B) Invading a host cell that sends an inhibitory signal to immune cells allows pathogens more time to replicate safely. (Ba) A host cell sends no net signal to the immune system at the initiation of the pathological process (t = 0). This is true of several cell types, such as beta cells in the pancreas as well as some cells in immune privileged sites throughout the body. The time that the host cell takes to produce a signal that is sufficient to activate immune cells is termed tA. (Bb) If the host cell sends an inhibitory signal to the immune system at baseline (through its expression of a shared ligand), then the same processes that induce immune-activating signals will take longer to cross the threshold required to activate the immune system (tB > tA). This lag period (tB − tA) allows for greater viral replication and increased pathology to develop before immune intervention (blue portion of the graph). In turn, the larger viral population is more likely to survive immune attack. Onset of immunopathology is indicated by the red portion of the graph.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ni L., Dong C. New checkpoints in cancer immunotherapy. Immunol. Rev. 2017;276:52–65. - PubMed
    1. Bulfone-Paus S. Positive and negative signals in mast cell activation. Trends Immunol. 2017;38:657–667. - PubMed
    1. Guillerey C. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 2016;17:1025–1036. - PubMed
    1. Barclay A.N., Hatherley D. The counterbalance theory for evolution and function of paired receptors. Immunity. 2008;29:675–678. - PMC - PubMed
    1. Colonna M., Samaridis J. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science. 1995;268:405–408. - PubMed

Publication types