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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    • "Interestingly, there is evidence that B220 (an alternatively spliced and heavily glycosylated product of Cd45) contributes toward defining the number of mNK cells in secondary lymphoid organs, as well as their ability to produce cytokines. Indeed, NK-cell numbers are increased in CD45-deficient mice, and CD45-deficient NK cells show a selective impairment in ITAM-based receptor cytokine production (48–50). Hence, it is tempting to suggest that lack of B220 expression deregulates pre-mNK cells, thereby promoting an altered NK-cell differentiation pathway. "
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    • "This could occur either through serine/threonine phosphorylation which is mediated by MAP kinases, or through tyrosine phosphorylation mediated by Pyk2, FAK and SFK. Both the MAP kinases and the tyrosine kinases Pyk2, FAK and SFK have been shown to be regulated by CD45 and may be disregulated in the absence of this protein [8], [9], [41], [80], [81], [82], [83], [84]. "
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