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RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems

Abstract

The immune system consists of two evolutionarily different but closely related responses, innate immunity and adaptive immunity. Each of these responses has characteristic receptors—Toll-like receptors (TLRs) for innate immunity and antigen-specific receptors for adaptive immunity. Here we show that the caspase recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK, CARDIAK, CCK and Ripk2)1,2,3,4 transduces signals from receptors of both immune responses. Rip2 was recruited to TLR2 signalling complexes after ligand stimulation. Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to signalling through interleukin (IL)-1 and IL-18 receptors, and deficient for signalling through Nod proteins—molecules also implicated in the innate immune response. Furthermore, Rip2-deficient T cells showed severely reduced NF-κB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (TH1) cells, indicating that Rip2 is required for optimal TCR signalling and T-cell differentiation. Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems.

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Figure 1: Expression of Rip2 in macrophages and targeted disruption of the mouse Rip2 gene.
Figure 2: Impaired TLR responses in Rip2-deficient cells.
Figure 3: Rip2 is required for optimal TLR signalling.
Figure 4: Rip2 is essential for activation of NF-κB by Nod1 and Nod2.
Figure 5: Rip2 is required for optimal IL-1/IL-18 receptor signalling in NK cells and TH1 effector CD4 T cells.
Figure 6: Rip2 is required for optimal NF-κB activation, IL-2 production and T-cell proliferation on TCR stimulation.

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Acknowledgements

We thank C. L. Stewart and M. Schnare for providing reagents; L. Evangelisti for technical assistance; and F. Manzo and G. Chenell for manuscript preparation. This work was supported by grants from the National Institutes of Health (G.N., J.G., C.A.J., R.M. and R.A.F) and from the Howard Hughes Medical Institute (C.A.J., R.M. and R.A.F.). K.K. is a recipient of a Postdoctoral Fellowship of the Cancer Research Institute; L.D.H. was supported by a fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchel Foundation; and R.A.F. and C.A.J are Investigators and R.M. is an Assistant Investigator of the Howard Hughes Medical Institute.

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Correspondence to Richard A. Flavell.

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Kobayashi, K., Inohara, N., Hernandez, L. et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194–199 (2002). https://doi.org/10.1038/416194a

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