Kobayashi Koichi, Inohara Naohiro, Hernandez Lorraine D, Galán Jorge E, Núñez Gabriel, Janeway Charles A, Medzhitov Ruslan, Flavell Richard A
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2002 Mar 14;416(6877):194-9. doi: 10.1038/416194a.
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) 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-kappaB 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.
免疫系统由两种在进化上不同但密切相关的反应组成，即固有免疫和适应性免疫。这些反应中的每一种都有其特征性受体——固有免疫的Toll样受体（TLR）和适应性免疫的抗原特异性受体。在此我们表明，含半胱天冬酶招募结构域（CARD）的丝氨酸/苏氨酸激酶Rip2（也称为RICK、CARDIAK、CCK和Ripk2）转导来自这两种免疫反应受体的信号。配体刺激后，Rip2被招募到TLR2信号复合物中。此外，用脂多糖、肽聚糖和双链RNA刺激TLR时，Rip2缺陷细胞中的细胞因子产生减少，但用细菌DNA刺激时则不然，这表明Rip2在TLR2/3/4下游而非TLR9下游。Rip2缺陷细胞对通过白细胞介素（IL）-1和IL-18受体的信号传导也反应低下，并且通过Nod蛋白（也与固有免疫反应有关的分子）的信号传导存在缺陷。此外，Rip2缺陷的T细胞在T细胞受体（TCR）结合时显示出严重降低的核因子κB激活、IL-2产生和增殖，以及向辅助性T细胞1（TH1）亚型细胞分化受损，这表明Rip2是最佳TCR信号传导和T细胞分化所必需的。因此，Rip2是固有免疫系统和适应性免疫系统信号的转导器和整合器。
