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SHIP influences signals from CD48 and MHC class I ligands that regulate NK cell homeostasis, effector function, and repertoire formation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 May 01; Vol. 184 (9), pp. 5065-74. Date of Electronic Publication: 2010 Apr 02. - Publication Year :
- 2010
-
Abstract
- 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-gamma 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-gamma 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-2(d) 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-gamma like their H2b(+) or 2B4(-/-) counterparts, demonstrating a uniform requirement for SHIP in induction of IFN-gamma 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.
- Subjects :
- Animals
Antigens, CD genetics
Antigens, CD metabolism
CD48 Antigen
Cell Lineage genetics
Cell Lineage immunology
Female
H-2 Antigens physiology
Homeostasis genetics
Inositol Polyphosphate 5-Phosphatases
Interferon-gamma biosynthesis
Interferon-gamma physiology
Killer Cells, Natural enzymology
Killer Cells, Natural metabolism
Ligands
Male
Mice
Mice, Knockout
Phosphoric Monoester Hydrolases deficiency
Phosphoric Monoester Hydrolases genetics
Phosphoric Monoester Hydrolases metabolism
Receptors, Immunologic deficiency
Receptors, Immunologic genetics
Receptors, Immunologic metabolism
Receptors, Immunologic physiology
Receptors, Natural Killer Cell metabolism
Receptors, Natural Killer Cell physiology
Signal Transduction genetics
Signaling Lymphocytic Activation Molecule Family
Antigens, CD physiology
Cytotoxicity, Immunologic genetics
H-2 Antigens metabolism
Homeostasis immunology
Killer Cells, Natural immunology
Phosphoric Monoester Hydrolases physiology
Receptors, Natural Killer Cell biosynthesis
Signal Transduction immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 184
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 20363967
- Full Text :
- https://doi.org/10.4049/jimmunol.0901862