The mechanism of activation of NK-cell IFN-gamma production by ligation of CD28

Mol Immunol. 1999 Apr;36(6):361-72. doi: 10.1016/s0161-5890(99)00051-6.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism*
  • Female
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Killer Cells, Natural / metabolism*
  • Kinetics
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • RNA, Messenger / metabolism
  • Receptors, IgG / metabolism
  • Transcription, Genetic
  • Tumor Cells, Cultured


  • Antigens, CD
  • CD28 Antigens
  • Fc gamma receptor IIB
  • RNA, Messenger
  • Receptors, IgG
  • Interferon-gamma