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

被引:741
作者
Kobayashi, K
Inohara, N
Hernandez, LD
Galán, JE
Núñez, G
Janeway, CA
Medzhitov, R
Flavell, RA
机构
[1] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[3] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
[5] Yale Univ, Sch Med, Boyer Ctr Mol Med, Ctr Microbial Pathogenesis, New Haven, CT 06536 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/416194a
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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)(1-4) 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-kappaB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (T(H)1) 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.
引用
收藏
页码:194 / 199
页数:6
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