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

Koichi Kobayashi, Naohiro Inohara, Lorraine D. Hernandez, Jorge E. Galán, Gabriel Núñez, Charles A. Janeway, Ruslan Medzhitov and Richard A. Flavell ()
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Koichi Kobayashi: Yale University School of Medicine
Naohiro Inohara: University of Michigan Medical School
Lorraine D. Hernandez: Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of Medicine
Jorge E. Galán: Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of Medicine
Gabriel Núñez: University of Michigan Medical School
Charles A. Janeway: Yale University School of Medicine
Ruslan Medzhitov: Yale University School of Medicine
Richard A. Flavell: Yale University School of Medicine

Nature, 2002, vol. 416, issue 6877, 194-199

Abstract: 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.

Date: 2002
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DOI: 10.1038/416194a

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