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T cell–intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii

Nature Immunology volume 10, pages 1267–1274 (2009)Cite this article

Abstract

Nod2 belongs to the nucleotide-binding oligomerization domain receptor (NLR) family of proteins, which function as intracellular pathogen sensors in innate immune cells. Nod2 deficiency results in an impaired immune response to bacterial pathogens. However, how this protein promotes host defense against intracellular parasites is unknown. Here we found that Nod2−/− mice had less clearance of Toxoplasma gondii and lower interferon-γ (IFN-γ) production. Reconstitution of T cell–deficient mice with Nod2−/− T cells followed by T. gondii infection demonstrated a T cell–intrinsic defect. Nod2−/− CD4+ T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel. Our data demonstrate a T cell–intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.

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Figure 1: Nod2 in host defense against T. gondii infection.
Figure 2: Nod2-deficient mice show impaired IFN-γ production despite normal IL-12p40 production.
Figure 3: Nod2-deficient mice show impaired type 1 immune responses during T. gondii infection.
Figure 4: DC function during T. gondii infection is unaffected by the absence of Nod2.
Figure 5: Nod2−/− CD4 cells have an intrinsic defect in IFN-γ production.
Figure 6: Impaired helper T cell differentiation and IL-2 production by Nod2−/− T cells.
Figure 7: Role of Nod2 in T cell–induced colitis.
Figure 8: Nod2 interacts with c-Rel and enhances Il2 transcription.

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Acknowledgements

We thank A. Weiss (University of California, San Francisco) for the pCD28RE/AP-1 luc reporter plasmid; G.Y. Chen for critically reading the manuscript; S. Koonse for assistance with managing mice colonies; the University of Michigan Flow Cytometry and the immunology core facilities for assistance with flow cytometry and enzyme-linked immunosorbent assay (ELISA); and G.S. Yap for discussions. Supported by the US National Institutes of Health (R01 DK61707; and T32-HL007517 to M.H.S.), the Swiss National Science Foundation (T.R.), the University of Michigan Comprehensive Cancer Center (Y.-G.K.), the Spanish Ministerio de Ciencia e Innovacion (SAF2007-61716 to M.F.), European Union (Eicosanox, for M.F.), Comunidad de Madrid (S-SAL-0159/2006 to M.F.) and La Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RD06/0014/1013 to M.F.).

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Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Michael H Shaw, Thornik Reimer, Neil Warner, Yun-Gi Kim & Gabriel Nuñez

  2. Centro de Biología Molecular, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain

    Carmen Sánchez-Valdepeñas & Manuel Fresno

Authors
  1. Michael H Shaw
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  7. Gabriel Nuñez
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Contributions

M.H.S. developed the concept and designed experiments; C.S.-V. and M.F. designed and did Jurkat and CD28RE–AP-1 assays; T.R., N.W. and Y.-G.K. provided technical support and conceptual advice; M.H.S. and G.N. prepared the manuscript; G.N. directed the research; and all authors discussed the results and implications and commented on the manuscript at all stages.

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Correspondence to Gabriel Nuñez.

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Shaw, M., Reimer, T., Sánchez-Valdepeñas, C. et al. T cell–intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol 10, 1267–1274 (2009). https://doi.org/10.1038/ni.1816

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