SHIP influences signals from CD48 and MHC class I ligands that regulate NK cell homeostasis, effector function, and repertoire formation.
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.
Fortenbery
Nicole R
NR
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Paraiso
Kim H T
KH
Taniguchi
Masaru
M
Brooks
Colin
C
Ibrahim
Leina
L
Kerr
William G
WG
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071178:CD48 Antigen; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D006183:H-2 Antigens / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; D000071178:CD48 Antigen; C490007:Cd244a protein, mouse; C000604066:Cd48 protein, mouse; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D008024:Ligands; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases