Enhanced NK-cell development and function in BCAP-deficient mice.
In B lymphocytes, the B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) facilitates signaling from the antigen receptor. Mice lacking BCAP have a predominantly immature pool of B cells with impaired immune function and increased susceptibility to apoptosis. Unexpectedly, we have found that natural killer (NK) cells from BCAP-deficient mice are more mature, more long-lived, more resistant to apoptosis, and exhibit enhanced functional activity compared with NK cells from wild-type mice. Surprisingly, these effects are evident despite a severe impairment of the immunoreceptor tyrosine-based activation motif-mediated Akt signaling pathway. The seemingly paradoxical phenotype reveals inherent differences in the signals controlling the final maturation of B cells and NK cells, which depend on positive and negative signals, respectively. Both enhanced interferon-gamma responses and augmented maturation of NK cells in BCAP-deficient mice are independent of available MHC class I ligands. Our data support a model in which blunting of BCAP-mediated activation signaling in developing NK cells promotes functionality, terminal maturation, and long-term survival.
MacFarlane
Alexander W
AW
Fox Chase Cancer Center, Division of Basic Science, Institute for Cancer Research, Philadelphia, PA 19111-2497, USA.
Yamazaki
Tetsuo
T
Fang
Min
M
Sigal
Luis J
LJ
Kurosaki
Tomohiro
T
Campbell
Kerry S
KS
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D016922:Cellular Senescence; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017634:Self Tolerance; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C487978:Pik3ap1 protein, mouse; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt