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Published on: January 7, 2019
Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints
Avishai Shemesh1,2, Michael Brusilovsky3, Kiran Kundu1,2
1The Shraga Segal Department of Microbiology, Immunology and Genetics, Goldman Building, Room 143, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 84105, Israel.
Abstract:
The natural cytotoxicity receptors (NCRs; NKp30, NKp44, and NKp46) were first defined as activating receptors on human NK cells that are important in recognition of and response to tumors. A flurry of recent research, however, has revealed that differential splicing can occur during transcription of each of the NCR genes, resulting in some transcripts that encode receptor isoforms with inhibitory functions. These alternative transcripts can arise in certain tissue microenvironments and appear to be induced by cytokines. Evidence indicates that some of the inhibitory NCRs are triggered by specific ligands, such as the interaction of the inhibitory isoform of NKp44 with PCNA on the surface of tumor cells. Here, we review the different NCR splice variants, cytokines that modulate their expression, their functional impacts on innate immune cells, and their differential expression in the contexts of cancer, pregnancy, and infections. The recent discovery of these inhibitory NCR isoforms has revealed novel innate immune checkpoints, many of which still lack defined ligands and clear mechanisms driving their expression. These NCR checkpoint pathways offer exciting potential therapeutic targets to manipulate innate immune functions under defined pathological conditions, such as cancer, pregnancy disorders, and pathogen exposure.
Insights
Natural cytotoxicity receptors (NCRs) can have inhibitory functions due to alternative splicing. These newly discovered inhibitory NCRs act as immune checkpoints and offer potential therapeutic targets for diseases like cancer.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Natural cytotoxicity receptors (NCRs) like NKp30, NKp44, and NKp46 were initially identified as activating receptors on NK cells crucial for anti-tumor responses.
- Recent studies reveal that alternative splicing of NCR genes generates isoforms with inhibitory functions.
Purpose of the Study:
- To review the diverse NCR splice variants and the cytokines that regulate their expression.
- To explore the functional consequences of these isoforms on innate immune cells.
- To discuss their differential expression in cancer, pregnancy, and infectious diseases.
Main Methods:
- Literature review of studies on NCR splice variants.
- Analysis of cytokine-mediated regulation of NCR expression.
- Examination of functional impacts and expression patterns in various pathological contexts.
Main Results:
- Differential splicing of NCR genes leads to inhibitory receptor isoforms.
- These inhibitory isoforms can be induced by cytokines in specific tissue microenvironments.
- The inhibitory NKp44 isoform interacts with PCNA on tumor cells, highlighting specific ligand-receptor interactions.
Conclusions:
- The discovery of inhibitory NCR isoforms reveals novel innate immune checkpoints.
- Many of these checkpoints lack defined ligands and clear regulatory mechanisms.
- These pathways present potential therapeutic targets for modulating innate immunity in cancer, pregnancy disorders, and infections.
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