IL-15 alters expression and function of the chemokine receptor CX3CR1 in human NK cells.
The chemokine receptor CX3CR1 is thought to regulate inflammation in part by modulating NK cell adhesion, migration, and killing in response to its ligand CX3CL1 (fractalkine). Recent reports indicate that IL-15, which is essential for development and survival of NK cells, may negatively regulate CX3CR1 expression, however, the effects of the cytokine on human NK cell CX3CR1 expression and function have not been fully delineated. Here, we demonstrate that short term culture in IL-15 decreases surface expression of CX3CR1 on cultured CD56+ cells from human blood resulting in diminished chemotaxis and calcium flux in response to CX3CL1. Cells cultured long term in IL-15 (more than five days) completely lost surface expression as well as mRNA and protein for CX3CR1. The effect was specific since mRNA for CCR5 was increased and mRNA for CXCR4 was unchanged in these cells by IL-15. Thus, exogenous IL-15 is a negative regulator of CX3CR1 expression and function in human CD56+ NK cells. The data imply that the use of IL-15 alone to expand NK cells ex vivo for immunotherapy may produce cells impaired in their ability to traffic to sites of inflammation.
Sechler
Joan M
JM
Molecular Signaling Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Barlic
Jana
J
Grivel
Jean-Charles
JC
Murphy
Philip M
PM
D015153:Blotting, Western; D019002:CD56 Antigen / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D002118:Calcium / Q000276:immunology; D002455:Cell Division; D002633:Chemotaxis / Q000276:immunology; D005434:Flow Cytometry; D005470:Fluorometry; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019002:CD56 Antigen; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019409:Interleukin-15; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D012313:RNA; D002118:Calcium