Submitted August 16, 2007
Accepted March 9, 2008
Enhanced NK cell development and function in BCAP-deficient mice
Alexander W MacFarlane IV, Tetsuo Yamazaki, Min Fang, Luis J. Sigal, Tomohiro Kurosaki, and Kerry S. Campbell*
Division of Basic Science, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, United States
Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan
* Corresponding author; email: kerry.campbell{at}fccc.edu.
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 NK cells from BCAP-deficient mice are more mature, more long-lived, more resistant to apoptosis, and exhibit enhanced functional activity as compared to NK cells from wild type mice. Surprisingly, these effects are evident despite a severe impairment of the ITAM-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 IFN-
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.
