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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Genhong Cheng.

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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). https://doi.org/10.1038/416190a

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