Dysregulation of signaling pathways in CD45-deficient NK cells leads to differentially regulated cytotoxicity and cytokine production

Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(18):7012-7. DOI: 10.1073/pnas.0601851103
Source: PubMed


CD45, a protein tyrosine phosphatase that regulates Src family kinases, is important for regulating T cell and B cell receptor signaling; however, little is known about how CD45 regulates immunoreceptor tyrosine-based activation motif (ITAM)-dependent natural killer (NK) cell receptor signaling and the resulting effector functions. NK cells from CD45-deficient mice are relatively competent for ITAM receptor-induced cell-mediated cytotoxicity, yet completely deficient for cytokine secretion after stimulation with ligands to or antibodies against NK1.1, CD16, Ly49H, Ly49D, and NKG2D. This deficiency in cytokine/chemokine production occurs at the level of mRNA expression. After receptor engagement, extracellular signal-regulated kinase and c-Jun N-terminal kinase activation was markedly perturbed, whereas p38 activation was not substantially affected. The pattern and amounts of basal tyrosine phosphorylation were altered in freshly isolated NK cells and were surprisingly and markedly increased in IL-2-expanded NK cells from CD45-/- mice. These findings indicate that CD45-dependent regulation of ITAM-dependent signaling pathways is essential for NK cell-mediated cytokine production but not cytolytic activity.

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Available from: Arthur Weiss, Aug 25, 2014
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    • "We found that CD45RARO NK cells show maximal degranulation and trogocytosis, suggesting that expression of both CD45RA and CD45RO isoforms might give to NK cells the appropriate level of CD45 activity for efficient signaling to boost cytotoxicity. CD45 is required for full NK cell cytotoxicity in vivo in mice (Hesslein et al., 2011); however, it is not required in vitro (Mason et al., 2006; Hesslein et al., 2006; Huntington et al., 2005). In agreement, we observed that other NK cell subsets, which express different CD45 isoforms, improved degranulation in vitro. "
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