Introduction

Although the developmental pathway of B and T lymphocytes is now understood in considerable detail, the factors and events that control the development of the third major population of lymphocytes found in humans and other vertebrate species, NK cells, are still unclear.  One of the key issues is the nature of the growth factors and receptors that support the proliferative expansion of  immature NK cells.  Of considerable importance in this regard has been the discovery that mice deficient in expression of gc have moderate numbers of B cells and T cells but no detectable NK cells (1, 2).  gc forms part of the receptors for several cytokines, including IL2, IL4, IL7, IL9, IL15 (3), the recently discovered IL21 (4), and possibly other as yet unknown cytokines and signalling molecules, implying that one or more of these gc-containing receptors plays a critical role in NK cell development.

The ability of IL2 to promote the growth and activation of mature NK cells makes IL2 an attractive candidate.  Indeed, numerous  in vitro studies have shown that IL2 can promote the development of NK cells from immature cells obtained from human (5, 6) and mouse (7-9) bone marrow and from human (10) and mouse (11, 12) fetal liver and thymus.  Furthermore, IL2-deficient humans (13) and mice (14) have markedly reduced levels of NK cells and NK cell functions, and both IL2Ra (15) and IL2Rb (16) deficient mice have greatly reduced numbers of NK cells.  However, IL2 and IL2Ra deficiency causes a general disturbance of lymphocyte homeostasis that could indirectly affect NK cell numbers and activity.  In addition, it is now known that the IL2Rb chain participates in the formation of receptors for another cytokine IL15.  In conjunction with gc, IL2Rb forms part of a low affinity receptor that binds IL15 with an association constant estimated at between 270pM and 2.5nM (17-20).  A high affinity receptor, involving the participation of the IL15Ra chain, has also been identified that binds IL15 with an affinity between 12 and 200pM (17-22).

Evidence that IL15 might be involved in NK cell development in vivo was initially suggested by the finding that mice lacking the transcription factor IRF1 that is required for IL15 production had a deficiency of NK cells that could be overcome, at least in vitro, by soluble IL15 (23).  More directly, IL15 (24) and IL15Ra (25) deficient mice were subsequently shown to lack readily detectable NK cells.  One explanation for these findings is that IL15 directly promotes the growth and differentiation of NK cell progenitors via high affinity IL15 receptors expressed on NK cells.  Several studies have shown that IL15 can indeed promote the development of NK cells from human (26) and mouse (27-29) progenitors in vitro.  However, in the absence of suitable antibodies against the IL15Ra chain there is currently no direct evidence that NK cells or their progenitors express IL15Ra at the cell surface.

A prediction of this hypothesis would be that the growth and differentiation of immature NK cells would occur at doses of IL15 sufficient to saturate high affinity IL15 receptors.  In the present study we report that although immature mouse NK cells can indeed proliferate vigorously and differentiate in response to soluble IL15 they do so only at doses much higher that those that would be required to saturate high affinity receptors.  Adult mouse NK cells can also not proliferate or be activated by low doses of soluble IL15 alone, nor surprisingly can mouse T cells.  These findings raise profound questions concerning the exact role of IL15 in promoting NK cell development and T cell homeostasis.  One possibility is that efficient interaction of IL15 with NK cells requires the participation of other cell bound or soluble factors.  In support of this we report here that low doses of IL21 enhance the responsiveness of immature and mature NK cells to suboptimal doses of IL15 and IL2.

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