The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations.
Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56(+)CD16(+)KIR(+) NK cells and a reciprocal increase in CD56(+)CD16(-)KIR(-) cells. These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca(2+) oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-gamma-producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56(+)KIR(-) NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.
Wang
Hongbo
H
Department of Pediatrics, Cancer Center, University of Minnesota, Minneapolis, USA.
Grzywacz
Bartosz
B
Sukovich
David
D
McCullar
Valarie
V
Cao
Qing
Q
Lee
Alisa B
AB
Blazar
Bruce R
BR
Cornfield
David N
DN
Miller
Jeffrey S
JS
Verneris
Michael R
MR
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD; D019002:CD56 Antigen; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006086:Graft vs Host Disease / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D020559:Monomeric GTP-Binding Proteins; D050778:NFATC Transcription Factors / Q000276:immunology; D017452:Receptors, IgG; D013997:Time Factors
D015703:Antigens, CD; D019002:CD56 Antigen; D016207:Cytokines; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D017452:Receptors, IgG; D016572:Cyclosporine; C490245:GEM protein, human; D020559:Monomeric GTP-Binding Proteins