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G protein-coupled receptors in natural killer cells
1Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Norway. maghazachi@basalmed.uio.no
Abstract:
Natural killer (NK) cells are capable of killing tumor as well as virally infected cells. How these cells migrate toward the infected sites in the body is not completely understood. Chemokine receptors that belong to the heptahelical family of receptors and characteristically bind heterotrimeric G proteins are present in most NK cells. Recent results showed that resting NK cells highly express constitutive chemokine receptors (CCR4, CCR7, CXCR4, and CX(3)CR1) with low expression of a limited repertoire of inflammatory chemokine receptors (CCR1 and CXCR3). However, only a subset of these cells expressing the CD56(dim) and adhesion molecule(high) phenotype is capable of in vivo binding to vascular endothelium. Under pathological conditions where inflammatory cytokines are present, these cells are induced to express inflammatory chemokine receptors. Resting as well as activated NK cells also express receptors for another member of the heptahelical family of receptors that bind phosphorylated or glycosylated lysolipids. These include sphingosine 1-phosphate (S1P)(1), S1P(4), and S1P(5), the receptors for S1P; lysophosphatidic acid (LPA)(1), LPA(2), and LPA(3), the receptors for LPA; and T cell death-associated gene 8, the receptor for psychosine. Similar to chemokines, S1P, LPA, and psychosine induce the chemotaxis of NK cells through heterotrimeric G proteins. However, in contrast to chemokines, which enhance the cytotoxicity of NK cells, lysolipids inhibit this function. We hope that gaining knowledge regarding the distribution of activated NK cells toward the sites of tumor growth or virally infected sites will give an advantage in designing strategies using these cells as tools for the prevention and treatment of immunodeficiencies.
Insights
Natural killer (NK) cells use chemokine and lysolipid receptors to migrate. Understanding NK cell migration to tumor or infected sites aids in developing immunodeficiency treatments.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Natural killer (NK) cells are crucial for eliminating tumor and virally infected cells.
- The precise mechanisms governing NK cell migration to infection sites remain incompletely understood.
- NK cells express various chemokine receptors, including CCR4, CCR7, CXCR4, and CX3CR1, with limited inflammatory receptor expression in resting states.
Purpose of the Study:
- To elucidate the migration patterns of NK cells towards pathological sites.
- To investigate the role of chemokine and lysolipid receptors in NK cell trafficking and function.
- To explore the potential of NK cells as therapeutic agents for immunodeficiencies.
Main Methods:
- Analysis of chemokine and lysolipid receptor expression on NK cells.
- Assessment of NK cell chemotaxis in response to chemokines and lysolipids.
- Evaluation of NK cell binding to vascular endothelium.
- Investigation of NK cell cytotoxicity modulation by chemokines and lysolipids.
Main Results:
- Resting NK cells express constitutive chemokine receptors (CCR4, CCR7, CXCR4, CX3CR1) and limited inflammatory receptors (CCR1, CXCR3).
- A subset of NK cells (CD56(dim), adhesion molecule(high)) binds to vascular endothelium, with induced inflammatory receptor expression under pathological conditions.
- NK cells express receptors for sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), which induce chemotaxis but inhibit cytotoxicity.
- Chemokines enhance NK cell cytotoxicity, while lysolipids inhibit it.
Conclusions:
- NK cell migration is mediated by both chemokine and lysolipid receptors, influencing their function.
- Understanding NK cell trafficking is vital for developing targeted immunotherapies.
- Targeting NK cell migration pathways could offer novel strategies for treating infections and cancers.