SHIP Influences Signals from CD48 and MHC Class I Ligands That Regulate NK Cell Homeostasis, Effector Function, and Repertoire Formation
| Autor: | Colin G. Brooks, Leina Ibrahim, William G. Kerr, Masaru Taniguchi, Kim H. T. Paraiso, Nicole Fortenbery |
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| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Male Immunology CD48 Antigen Ligands Major histocompatibility complex Interferon-gamma Mice Interleukin 21 Antigens CD Signaling Lymphocytic Activation Molecule Family MHC class I Animals Homeostasis Immunology and Allergy Cell Lineage Receptors Immunologic Receptor Mice Knockout biology Inositol Polyphosphate 5-Phosphatases H-2 Antigens CD48 NKG2D Phosphoric Monoester Hydrolases Cell biology Killer Cells Natural Cytolysis Interleukin 12 biology.protein Receptors Natural Killer Cell Female Signal Transduction |
| Zdroj: | The Journal of Immunology. 184:5065-5074 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Previously, we showed that 2B4 is a dominant inhibitory receptor in SHIP-deficient NK cells that prevents efficient cytolysis of complex targets. We show in this study that 2B4 deficiency restores homeostatic control and cytolytic function to SHIP-deficient NK cells. However, 2B4−/−SHIP−/− NK cells still exhibit a profound disruption of their NK receptor repertoire and are compromised for induction of IFN-γ by several NK-activating receptors, including NKp46, NK.1.1, and NKG2D. In addition, we find that 2B4−/− NK cells have an extensively disrupted repertoire, including a supernormal frequency of NKp46+ NK cells. Consequently IFN-γ is induced on a much higher percentage of 2B4−/− NK cells following engagement of NKp46. We also find that both SHIP and 2B4 are required to prevent expression of Ly49B, a myeloid lineage MHC class I receptor not normally expressed by the NK lineage. Finally, when SHIP-deficient NK cells are on an H-2d background, they exhibit supernormal levels of Ly49A and possess normal cytolytic function against MHC-matched tumor targets and enhanced cytolysis of MHC mismatched tumor targets. However, despite normal or elevated cytolytic function, H2d SHIP−/− NK cells exhibit poor induction of IFN-γ like their H2b+ or 2B4−/− counterparts, demonstrating a uniform requirement for SHIP in induction of IFN-γ downstream of key NK activating receptors. These findings reveal a complex interplay of SHIP, 2B4, and MHC in the regulation of homeostasis, effector function, and repertoire formation in the NK cell lineage. |
| Databáze: | OpenAIRE |
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