Involvement of receptor-interacting protein 2 in innate and adaptive immune responses


Host defences to microorganisms rely on a coordinated interplay between the innate and adaptive responses of immunity1. Infection with intracellular bacteria triggers an immediate innate response requiring macrophages, neutrophils and natural killer cells, whereas subsequent activation of an adaptive response through development of T-helper subtype 1 cells (TH1) proceeds during persistent infection1. To understand the physiological role of receptor-interacting protein 2 (Rip2), also known as RICK and CARDIAK, we generated mice with a targeted disruption of the gene coding for Rip2. Here we show that Rip2-deficient mice exhibit a profoundly decreased ability to defend against infection by the intracellular pathogen Listeria monocytogenes. Rip2-deficient macrophages infected with L. monocytogenes or treated with lipopolysaccharide (LPS) have decreased activation of NF-κB, whereas dominant negative Rip2 inhibited NF-κB activation mediated by Toll-like receptor 4 and Nod1. In vivo, Rip2-deficient mice were resistant to the lethal effects of LPS-induced endotoxic shock. Furthermore, Rip2 deficiency results in impaired interferon-γ production in both TH1 and natural killer cells, attributed in part to defective interleukin-12-induced Stat4 activation. Our data reflect requirements for Rip2 in multiple pathways regulating immune and inflammatory responses.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Generation of Rip2-deficient mice.
Figure 2: Impaired isotype switching and T-cell proliferation in Rip2-/- cells.
Figure 3: Impaired IL-12- and IL-18-induced activation of TH1 and NK cells in Rip2-/- mice.
Figure 4: Increased susceptibility to Listeria monocytogenes in Rip2-/- mice.
Figure 5: Impaired NF-κB activation in macrophages of Rip2-/- mice.


  1. 1

    Medzhitov, R. & Janeway, C. A. Jr. Innate immune recognition and control of adaptive immune responses. Semin. Immunol. 10, 351–353 (1998).

    CAS  Article  Google Scholar 

  2. 2

    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).

    CAS  Article  Google Scholar 

  3. 3

    Inohara, N., del Peso, L., Koseki, T., Chen, S. & Núñez, 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); erratum J. Biol. Chem. 273, 18675 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Thome, M. et al. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr. Biol. 8, 885–888 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Yip, H. C. et al. Adjuvant-guided type-1 and type-2 immunity: infectious/noninfectious dichotomy defines the class of response. J. Immunol. 162, 3942–3949 (1999).

    CAS  PubMed  Google Scholar 

  6. 6

    Finkelman, F. D. et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8, 303–333 (1990).

    CAS  Article  Google Scholar 

  7. 7

    Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    CAS  Article  Google Scholar 

  8. 8

    Paul, W. E. & Seder, R. A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Yang, J., Murphy, T. L., Ouyang, W. & Murphy, K. M. Induction of interferon-gamma production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation. Eur. J. Immunol. 29, 548–555 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Thierfelder, W. E. et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Kaplan, M. H., Sun, Y. L., Hoey, T. & Grusby, M. J. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382, 174–177 (1996).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Trinchieri, G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Dai, W. J. et al. Impaired macrophage listericidal and cytokine activities are responsible for the rapid death of Listeria monocytogenes-infected IFN-γ receptor-deficient mice. J. Immunol. 158, 5297–5304 (1997).

    CAS  PubMed  Google Scholar 

  14. 14

    DiTirro, J. et al. Disruption of the cellular inflammatory response to Listeria monocytogenes infection in mice with disruptions in targeted genes. Infect. Immun. 66, 2284–2289 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Inohara, N., Ogura, Y., Chen, F. F., Muto, A. & Nuñez, G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J. Biol. Chem. 276, 2551–2554 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Hugot, J. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    ADS  CAS  Article  Google Scholar 

  17. 17

    Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Inohara, N. et al. An induced proximity model for NF-κB activation in the Nod1/RICK and RIP signaling pathways. J. Biol. Chem. 275, 27823–27831 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    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).

    CAS  Article  Google Scholar 

  20. 20

    Girardin, S. E. et al. CARD4/Nod1 mediates NF-κB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2, 736–742 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Reiner, S. L., Zheng, S., Corry, D. B. & Locksley, R. M. Constructing polycompetitor cDNAs for quantitative PCR. J. Immunol. Methods 165, 37–46 (1993); erratum J. Immunol. Methods 173, 133; 175, 275 (1994).

    CAS  Article  Google Scholar 

  22. 22

    Khan, K. D. et al. Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc. Natl Acad. Sci. USA 90, 6806–6810 (1993).

    ADS  CAS  Article  Google Scholar 

Download references


We thank V. Dixit for human RIP2 cDNA; T. Parks for Nod1 cDNA; T. Roni and S. Smale for CD4-TLR4 cDNA; K. Shaui and X.-F. Qin for reagents and advice; and R. L. Modlin for critical reading of the manuscript. A.I.C. is supported by the Medical Scientist Training Program; P.W.D. is a Lymphoma and Leukemia Society Research Fellow; and G.C. is a Lymphoma and Leukemia Society Research Scholar.

Author information



Corresponding author

Correspondence to Genhong Cheng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chin, A., Dempsey, P., Bruhn, K. et al. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 416, 190–194 (2002).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.