Abstract
CRACC is a self-associating member of the signaling lymphocytic activation molecule family that is expressed on cells of the immune system, including natural killer cells and activated T cells. Here we examine the function and mechanism of action of CRACC using several complementary approaches, including the generation of a CRACC-deficient mouse. Our results demonstrate that CRACC positively regulated natural killer cell functions by a mechanism dependent on the adaptor EAT-2 but not the related adaptor SAP. However, in the absence of EAT-2, CRACC potently inhibited natural killer cell function. CRACC was also inhibitory in T cells, which are typically devoid of EAT-2. Thus, CRACC can exert activating or inhibitory influences on cells of the immune system depending on cellular context and the availability of effector proteins.
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Acknowledgements
We thank S. Latour for critical reading of the manuscript; J. Drouin (Clinical Research Institute of Montreal) for pJA1617; and J. Penninger (Institute for Molecular Biotechnology) for pCAGGS-Flpe. Supported by the Canadian Institutes of Health Research (A.V. and Z.D.), the Canadian Cancer Society (A.V. and M.-E.C.-M.), the Howard Hughes Medical Institute (A.V.), the Cancer Research Society (M.-E.C.-M.), the Canada Research Chair Program (A.V.), the Clinical Research Institute of Montreal (Z.D.) and the Terry Fox Foundation (M.-E.C.-M.).
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M.-E.C.-M. conceived research, did experiments, analyzed data and wrote the manuscript; Z.D. conceived research, did experiments and generated critical reagents; X.S. and S.Z. did research and generated critical reagents; and A.V. conceived research, analyzed data and wrote the manuscript.
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Cruz-Munoz, ME., Dong, Z., Shi, X. et al. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol 10, 297–305 (2009). https://doi.org/10.1038/ni.1693
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DOI: https://doi.org/10.1038/ni.1693
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