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Blood, 1 July 2008, Vol. 112, No. 1, pp. 8-9. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Held, W. Search for Related Content PubMed PubMed Citation Articles by Held, W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on MacFarlane et al, page 131 Inhibitions in NK-cell maturation Werner Held LUDWIG INSTITUTE FOR CANCER RESEARCH, LAUSANNE BRANCH Adaptor molecules serve as intracellular protein-protein interaction platforms that are required to amplify and diversify signals received at the plasma membrane. Accordingly, adaptors play important roles for lymphocyte development and function. B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a cytosolic adaptor that connects the B-cell receptor (BCR) to the phosphatidylinositol 3-kinase (PI3K) pathway.1 Mice deficient for BCAP have reduced numbers of mature B cells, which expand poorly in response to BCR stimulation.2 This is accounted for, in part, by an increase in activation-induced B-cell death in vitro, which translates into a reduced life span of mature B cells in vivo.2 Indeed, the antibody response to T cell–independent antigens is strongly reduced in the absence of BCAP. Thus, in B cells, BCAP deficiency results in a loss-of-function phenotype. In this issue of Blood, MacFarlane and colleagues show that the role of BCAP for natural killer (NK) cells differs substantially from that seen in B cells. The absence of BCAP results in an expanded peripheral NK-cell pool, and more of these cells display a mature phenotype. In further contrast to the B-cell phenotype, BCAP deficiency renders mature NK cells more resistant to apoptosis. Finally, NK cells lacking BCAP show an increase in effector function, including enhanced production of the cytokine IFN-. Clearly, more work will be necessary to understand the molecular basis for how BCAP supports B cells while attenuating NK cells. In B cells, it has been shown that BCAP is needed to maintain normal expression of c-Rel,2 an NF-B family protein mediating the survival and the proliferation of mature B cells. Along this line, it will be interesting to see whether BCAP influences the expression of NF-B family proteins in NK cells. Consistent with this possibility, an enhanced IFN- response, as seen in BCAP-deficient NK cells, has also been observed in mice lacking NF-B1 (p50).3 Irrespective of the precise basis, the inhibitory effect of BCAP raises the prospect of using BCAP blockade to boost NK-cell reactions. As suggested by the authors, accelerated maturation and increased efficacy of NK cells may enhance graft-versus-leukemia effects in patients receiving hematopoietic stem cell transplants. The work by MacFarlane and colleagues provides unexpected insights into an additional aspect of NK-cell biology: the role of MHC class I recognition in NK-cell maturation and the acquisition of functional competence (also termed licensing). In the absence of MHC class I molecules, NK-cell maturation (as judged by the down-regulation of CD27) is inefficient, and the ability of NK cells to produce IFN- or to kill is low. NK-cell function improves when inhibitory receptors display specificity for self–MHC class I molecules. Surprisingly, BCAP deficiency improved NK-cell maturation and function in the absence of MHC class I molecules. This suggests a model in which BCAP keeps NK cells immature. Inhibition of BCAP function, perhaps due to the engagement of MHC class I receptors during NK-cell development, may allow NK-cell maturation. As usual, unexpected findings raise further questions. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity. 2000;13:817–827.[CrossRef][Medline] [Order article via Infotrieve] Yamazaki T, Kurosaki T. Contribution of BCAP to maintenance of mature B cells through c-Rel. Nat Immunol. 2003;4:780–786.[CrossRef][Medline] [Order article via Infotrieve] Tato CM, Mason N, Artis D, et al. Opposing roles of NF-kappaB family members in the regulation of NK cell proliferation and production of IFN-gamma. Int Immunol. 2006;18:505–513.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Blood 2008 112: 131-140. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Held, W. Search for Related Content PubMed PubMed Citation Articles by Held, W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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