The mechanism of activation of NK-cell IFN-gamma production by ligation of CD28.
We have investigated the mechanism by which anti-CD28 antibodies activates IFN-gamma production by murine NK cells. These studies reveal that engagement of CD28 alone by this antibody is a poor activator of this cytokine response. Effective stimulation requires simultaneous ligation of the receptor for Fc (FcgammaRIII, CD16) which on its own is also a poor inducer of murine NK cells. The mechanism by which immobilized anti-CD28 increases IFN-gamma mRNA abundance involves both upregulation of transcription as well as induction of mRNA stabilization. However, the elevation of transcription is not as evident as that induced by IL-12 which, in contrast, does not induce message stabilization. Thus ligation of CD28 in the presence of IL-12 results in a synergistic increase in production of the cytokine. Using this assay we have also determined that immobilized anti-CD28 cannot induce resting NK cells to produce IFN-gamma. In contrast, the same cells can be induced by BCL1-C11 tumor cells that express high amounts of the CD28 ligand, B7-2. These studies provide important insights into the ability of cells bearing counter-receptor for CD28 to activate NK cell-cytokine production in vivo.
Cheung
J C
JC
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Koh
C Y
CY
Gordon
B E
BE
Wilder
J A
JA
Yuan
D
D
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000378:metabolism*; D007700:Kinetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018106:CD28 Antigens; C080571:Fc gamma receptor IIB; D012333:RNA, Messenger; D017452:Receptors, IgG; D007371:Interferon-gamma