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Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function

Nature Immunology volume 10, pages 297–305 (2009)Cite this article

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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Figure 1: Expression of CRACC on mouse cells of the immune system.
Figure 2: Expression of CRACC on target cells enhances the natural cytotoxicity of mouse NK cells.
Figure 3: CRACC-deficient NK cells show impaired function in vitro and in vivo.
Figure 4: Regulation of CRACC-dependent cytotoxicity by EAT-2 but not by SAP.
Figure 5: Regulation of CRACC-mediated signaling by EAT-2 and ERT.
Figure 6: Mechanism of the activation and inhibition of NK cells by CRACC.
Figure 7: Mechanism of EAT-2-dependent CRACC function.
Figure 8: CRACC is inhibitory in CD4+ T cells, which lack EAT-2 and ERT.

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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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Author notes

  1. Department of Medicine, McGill University, Montréal, Québec, Canada H3G 1Y6.

Authors and Affiliations

  1. Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, H2W 1R7, Québec, Canada

    Mario-Ernesto Cruz-Munoz, Zhongjun Dong, Xiaochu Shi, Shaohua Zhang & André Veillette

  2. Department of Medicine, University of Montréal, Montréal, Québec, Canada, H3C 3J7.

    André Veillette

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  1. Mario-Ernesto Cruz-Munoz
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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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Correspondence to André Veillette.

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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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