The Journal of Experimental Medicine
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Published 2 May 2005. doi:10.1084/jem.20042294
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 9, 1421-1433
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ARTICLE

 A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells

Nicholas D. Huntington, Yuekang Xu, Stephen L. Nutt, and David M. Tarlinton

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia

CORRESPONDENCE Nicholas D. Huntington huntington{at}wehi.edu.au

Engagement of receptors on the surface of natural killer (NK) cells initiates a biochemical cascade ultimately triggering cytokine production and cytotoxicity, although the interrelationship between these two outcomes is currently unclear. In this study we investigate the role of the cell surface phosphatase CD45 in NK cell development and intracellular signaling from activating receptors. Stimulation via the major histocompatibility complex I–binding receptor, Ly49D on CD45–/– primary NK cells resulted in the activation of phosphoinositide-3-kinase and normal cytotoxicity but failed to elicit a range of cytokines and chemokines. This blockage is associated with impaired phosphorylation of Syk, Vav1, JNK, and p38, which mimics data obtained using inhibitors of the src-family kinases (SFK). These data, supported by analogous findings after CD16 and NKG2D stimulation of CD45–/– primary NK cells, place CD45 upstream of SFK in NK cells after stimulation via immunoreceptor tyrosine-based activation motif-containing receptors. Thus we identify CD45 as a pivotal enzyme in eliciting a precise subset of NK cell responses.

Abbreviations used: ADCC, antibody-dependent cell cytotoxicity; BrdU, bromodeoxyuridine; ITAM, immunoreceptor tyrosine-based activation motif; JNK, c-Jun NH2-terminal kinase; MCMV, murine cytomegalovirus; PI3K, phosphoinositide-3-kinase; Rae-1, retinoid acid early inducible transcript; SFK, src-family kinase.

S.L. Nutt and D.M. Tarlinton contributed equally to this work.


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