Inhibitions in NK-cell maturation

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-γ.

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-κB 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-κB family proteins in NK cells. Consistent with this possibility, an enhanced IFN-γ response, as seen in BCAP-deficient NK cells, has also been observed in mice lacking NF-κB1 (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-γ 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.