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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Inohara, N., del Peso, L., Koseki, T., Chen, S. & Nunez, G. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J. Biol. Chem. 273, 12296–12300 (1998).
McCarthy, J. V., Ni, J. & Dixit, V. M. RIP2 is a novel NF-κB-activating and cell death-inducing kinase. J. Biol. Chem. 273, 16968–16975 (1998).
Thome, M. et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr. Biol. 8, 885–888 (1998).
Medzhitov, R. & Janeway, C. Jr. Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000).
Kelliher, M. A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).
Demuth, A., Goebel, W., Beuscher, H. U. & Kuhn, M. Differential regulation of cytokine and cytokine receptor mRNA expression upon infection of bone marrow-derived macrophages with Listeria monocytogenes. Infect. Immun. 64, 3475–3483 (1996).
Humke, E. W., Shriver, S. K., Starovasnik, M. A., Fairbrother, W. J. & Dixit, V. M. ICEBERG: a novel inhibitor of interleukin-1β generation. Cell 103, 99–111 (2000).
Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).
Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).
Bertin, J. et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-κB. J. Biol. Chem. 274, 12955–12958 (1999).
Inohara, N. et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J. Biol. Chem. 274, 14560–14567 (1999).
Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812–4818 (2001).
Inohara, N., Ogura, Y., Chen, F. F., Muto, A. & Nunez, G. Human nod1 confers responsiveness to bacterial lipopolysaccharides. J. Biol. Chem. 276, 2551–2554 (2001).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
Girardin, S. E. et al. CARD4/Nod1 mediates NF-κB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2, 736–742 (2001).
Growney, J. D. & Dietrich, W. F. High-resolution genetic and physical map of the Lgn1 interval in C57BL/6J implicates Naip2 or Naip5 in Legionella pneumophila pathogenesis. Genome Res. 10, 1158–1171 (2000).
Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).
Miceli-Richard, C. et al. CARD15 mutations in Blau syndrome. Nature Genet. 29, 19–20 (2001).
Yang, J., Zhu, H., Murphy, T. L., Ouyang, W. & Murphy, K. M. IL-18-stimulated GADD45-β required in cytokine-induced, but not TCR-induced, IFN-γ production. Nature Immunol. 2, 157–164 (2001).
Leitenberg, D. & Bottomly, K. Regulation of naive T cell differentiation by varying the potency of TCR signal transduction. Semin. Immunol. 11, 283–292 (1999).
Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).
Sun, Z. et al. PKC-Θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).
Aronica, M. A. et al. Preferential role for NF-κ B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo. J. Immunol. 163, 5116–5124 (1999).
Celada, A., Gray, P. W., Rinderknecht, E. & Schreiber, R. D. Evidence for a γ-interferon receptor that regulates macrophage tumoricidal activity. J. Exp. Med. 160, 55–74 (1984).
Kobayashi, K., Hatano, M., Otaki, M., Ogasawara, T. & Tokuhisa, T. Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc. Natl Acad. Sci. USA 96, 1457–1462 (1999).
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.
The authors declare no competing financial interests.
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