CTLA-4 Is Expressed by Activated Mouse NK Cells and Inhibits NK Cell IFN-γ Production in Response to Mature Dendritic Cells
- 1 May 2014
- journal article
- Published by The American Association of Immunologists
- Vol. 192 (9), 4184-4191
- https://doi.org/10.4049/jimmunol.1302091
Abstract
NK cells express an array of activating and inhibitory receptors that determine NK cell responses upon triggering by cognate ligands. Although activating NK cell receptors recognize mainly ligands expressed by stressed, virus-infected, or transformed cells, most inhibitory receptors engage MHC class I, preventing NK cell activation in response to healthy cells. In this study, we provide insight into the regulation and function of additional receptors involved in mouse NK cell responses: CTLA-4 and CD28. CTLA-4 and CD28 engage the same ligands, B7-1 and B7-2, which are primarily expressed by APCs, such as dendritic cells. Our data demonstrate that activation of mouse NK cells with IL-2 induces the expression of CTLA-4 and upregulates CD28. CTLA-4 expression in IL-2–expanded NK cells was further up- or downregulated by IL-12 or TGF-β, respectively. Using gene-deficient NK cells, we show that CD28 induces, and CTLA-4 inhibits, IFN-γ release by NK cells upon engagement by the recombinant ligand, B7-1, or upon coculture with mature dendritic cells. Notably, we show that mouse NK cells infiltrating solid tumors express CD28 and CTLA-4 and respond to stimulation with recombinant B7-1, suggesting that the NK cell responses mediated by the CD28/CTLA-4:B7-1/B7-2 system could be of importance during malignant disease. Accordingly, our study might have implications for immunotherapy of cancer based on blocking anti–CTLA-4 mAbs.Keywords
This publication has 51 references indexed in Scilit:
- Controlling Natural Killer Cell Responses: Integration of Signals for Activation and InhibitionAnnual Review of Immunology, 2013
- Cutting Edge: Cell-Extrinsic Immune Regulation by CTLA-4 Expressed on Conventional T CellsPublished by The American Association of Immunologists ,2012
- Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK CellsCancer Research, 2012
- Complexities of TGF-β Targeted Cancer TherapyInternational Journal of Biological Sciences, 2012
- Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experienceCurrent Opinion in Virology, 2011
- Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4Science, 2011
- Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 familyImmunological Reviews, 2011
- The Interactions of Multiple Cytokines Control NK Cell MaturationThe Journal of Immunology, 2010
- TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progressionTrends in Immunology, 2010
- SYNERGISTIC PROLIFERATION AND ACTIVATION OF NATURAL KILLER CELLS BY INTERLEUKIN 12 AND INTERLEUKIN 18Cytokine, 1999