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NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells

Nature volume 484, pages 510–513 (2012)Cite this article

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A Corrigendum to this article was published on 25 November 2015

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Abstract

NLRs (nucleotide-binding domain leucine-rich-repeat-containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress1,2. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear2,3. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain, and has been postulated to be a negative regulator of other NLR members, including NLRP3 (refs 4–6). We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10−/− mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminium hydroxide and complete Freund’s adjuvant. Adaptive immunity was impaired in the absence of NLRP10 because of a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues, whereas upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and -independent ligands remained intact. The loss of antigen transport to the draining lymph nodes by a subset of migratory DCs resulted in an almost absolute loss in naive CD4+ T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.

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Figure 1: Nlrp10 −/− mice have a global defect in adaptive immune responses.
Figure 2: Nlrp10 −/− mice cannot mount T-cell-dependent adaptive immune responses.
Figure 3: Nlrp10 −/− dendritic cells do not take antigen to the draining lymph node.
Figure 4: Nlrp10 −/− dendritic cells cannot emigrate from inflamed tissue but remain responsive to chemokines.

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Gene Expression Omnibus

Data deposits

The microarray data discussed in this publication have been deposited in NCBI’s Gene ExpressionOmnibus and are accessible through GEO Series accession number GSE36009.

Change history

  • 25 November 2015

    Nature 484, 510–513 (2012); 10.1038/nature11012 In this Letter, we reported that NLRP10-deficient mice had no defect in inflammasome function in macrophages or dendritic cells (DCs). Instead, a loss of T-cell-dependent immune responses was seen in these mice secondary to a defect in DC migration. Wehave since noticed a change in the phenotype of the NLRP10-knockout mice involving DC migration, after backcrossing them onto backgrounds such as FVB or BALB/c (see Supplementary Methods).

References

  1. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010)

    Article  CAS  Google Scholar 

  2. Williams, A., Flavell, R. A. & Eisenbarth, S. C. The role of NOD-like receptors in shaping adaptive immunity. Curr. Opin. Immunol. 22, 34–40 (2010)

    Article  CAS  Google Scholar 

  3. Medzhitov, R. & Janeway, C. A., Jr Innate immune induction of the adaptive immune response. Cold Spring Harb. Symp. Quant. Biol. 64, 429–436 (1999)

    Article  CAS  Google Scholar 

  4. Imamura, R. et al. Anti-inflammatory activity of PYNOD and its mechanism in humans and mice. J. Immunol. 184, 5874–5884 (2010)

    Article  CAS  Google Scholar 

  5. Inohara, N. & Nunez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nature Rev. Immunol. 3, 371–382 (2003)

    Article  CAS  Google Scholar 

  6. Wang, Y. et al. PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Int. Immunol. 16, 777–786 (2004)

    Article  CAS  Google Scholar 

  7. Eisenbarth, S. C., Colegio, O. R., O’Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008)

    Article  CAS  ADS  Google Scholar 

  8. Li, H., Willingham, S. B., Ting, J. P. & Re, F. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008)

    Article  CAS  Google Scholar 

  9. Gris, D. et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974–981 (2010)

    Article  CAS  Google Scholar 

  10. Eisenbarth, S. C. et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645–1651 (2002)

    Article  CAS  Google Scholar 

  11. Bachmann, M. F., Hengartner, H. & Zinkernagel, R. M. T helper cell-independent neutralizing B cell response against vesicular stomatitis virus: role of antigen patterns in B cell induction? Eur. J. Immunol. 25, 3445–3451 (1995)

    Article  CAS  Google Scholar 

  12. Palm, N. W. & Medzhitov, R. Immunostimulatory activity of haptenated proteins. Proc. Natl Acad. Sci. USA 106, 4782–4787 (2009)

    Article  CAS  ADS  Google Scholar 

  13. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998)

    Article  CAS  ADS  Google Scholar 

  14. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004)

    Article  CAS  Google Scholar 

  15. Martin-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003)

    Article  CAS  Google Scholar 

  16. Saeki, H., Moore, A. M., Brown, M. J. & Hwang, S. T. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J. Immunol. 162, 2472–2475 (1999)

    CAS  PubMed  Google Scholar 

  17. Itano, A. A. et al. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19, 47–57 (2003)

    Article  CAS  Google Scholar 

  18. Jakubzick, C. et al. Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes. J. Exp. Med. 205, 2839–2850 (2008)

    Article  CAS  Google Scholar 

  19. Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010)

    Article  CAS  Google Scholar 

  20. Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009)

    Article  CAS  Google Scholar 

  21. Plantinga, M., Hammad, H. & Lambrecht, B. N. Origin and functional specializations of DC subsets in the lung. Eur. J. Immunol. 40, 2112–2118 (2010)

    Article  CAS  Google Scholar 

  22. Cyster, J. G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005)

    Article  CAS  Google Scholar 

  23. Czeloth, N., Bernhardt, G., Hofmann, F., Genth, H. & Forster, R. Sphingosine-1-phosphate mediates migration of mature dendritic cells. J. Immunol. 175, 2960–2967 (2005)

    Article  CAS  Google Scholar 

  24. Dieu, M. C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998)

    Article  CAS  Google Scholar 

  25. Gunn, M. D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999)

    Article  CAS  Google Scholar 

  26. Sallusto, F. et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760–2769 (1998)

    Article  CAS  Google Scholar 

  27. Noben-Trauth, N. et al. An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. Proc. Natl Acad. Sci. USA 94, 10838–10843 (1997)

    Article  CAS  ADS  Google Scholar 

  28. Zheng, B., Berrie, C. P., Corda, D. & Farquhar, M. G. GDE1/MIR16 is a glycerophosphoinositol phosphodiesterase regulated by stimulation of G protein-coupled receptors. Proc. Natl Acad. Sci. USA 100, 1745–1750 (2003)

    Article  CAS  ADS  Google Scholar 

  29. Arthur, J. C. et al. Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. J. Immunol. 185, 4515–4519 (2010)

    Article  CAS  Google Scholar 

  30. Ippagunta, S. K. et al. The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nature Immunol. 12, 1010–1016 (2011)

    Article  Google Scholar 

  31. Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006)

    Article  CAS  Google Scholar 

  32. Cohn, L., Homer, R. J., Niu, N. & Bottomly, K. T helper 1 cells and interferon γ regulate allergic airway inflammation and mucus production. J. Exp. Med. 190, 1309–1318 (1999)

    Article  CAS  Google Scholar 

  33. Laouar, Y. et al. TGF-β signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 10865–10870 (2008)

    Article  CAS  ADS  Google Scholar 

  34. Lutz, M. B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999)

    Article  CAS  Google Scholar 

  35. Jakubzick, C., Helft, J., Kaplan, T. J. & Randolph, G. J. Optimization of methods to study pulmonary dendritic cell migration reveals distinct capacities of DC subsets to acquire soluble versus particulate antigen. J. Immunol. Methods 337, 121–131 (2008)

    Article  CAS  Google Scholar 

  36. Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank R. Medzhitov and M. Albert for discussion and review of this manuscript, and F. Duffy for assistance with manuscript preparation. S.C.E. was supported by T32HL007974, K08AI085038 and Yale CTSA (UL1 RR024139). O.R.C. was supported by the Damon Runyon Cancer Research Foundation (DRG 108-09), the Yale CTSA (UL1 RR024139 and 5KL2RR024138), the Yale SPORE in Skin Cancer (1 P50 CA121974) and the Dermatology Foundation. E.E. is supported by Cancer Research Institute, the American Physicians for Medicine in Israel Foundation, and the United States-Israel binational Foundation grant. A.M.H., D.G.G. and in vivo imaging were supported by Yale Rheumatologic Disease Research Core Center P30AR053495. F.S.S. was supported by R01AI087630 and an Edward Mallinckrodt, Jr. Foundation scholarship. A.W. was a Howard Hughes fellow and R.A.F. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Stephanie C. Eisenbarth and Adam Williams: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Stephanie C. Eisenbarth, David G. Gonzalez, Lan Xu & Ann M. Haberman

  2. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Adam Williams, Till Strowig, Anthony Rongvaux, Jorge Henao-Mejia, Christoph A. Thaiss, Lauren A. Zenewicz, Eran Elinav & Richard A. Flavell

  3. Department of Dermatology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Oscar R. Colegio & Lan Xu

  4. Department of Pathology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Hailong Meng & Steven H. Kleinstein

  5. Department of Internal Medicine, Inflammation Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Sophie Joly & Fayyaz S. Sutterwala

  6. Interdepartmental Program in Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Steven H. Kleinstein

  7. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Richard A. Flavell

  8. Veterans Affairs Medical Center, Iowa City, 52241, Iowa, USA

    Fayyaz S. Sutterwala

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Contributions

S.C.E. and A.W. wrote the manuscript, designed, performed and interpreted experiments with technical assistance from L.X., F.S.S. generated Nlrp10−/− mice, S.J. performed in vitro inflammasome activation, O.R.C. and J.H.-M. assisted with trans-well assays and performed real-time PCR, L.A.Z. assisted with EAE experiments, T.S. assisted with TNP immunizations, A.R. assisted with intravenous LPS experiments, E.E. provided technical assistance with DC isolations, C.A.T. performed immunofluorescence experiments, H.M. and S.H.K. performed array analysis, D.G. and A.M.H. performed intravital microscopy and quantification. R.A.F. assisted in experimental design and interpretation. S.C.E. and R.A.F. directed the project.

Corresponding authors

Correspondence to Stephanie C. Eisenbarth or Richard A. Flavell.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-13. (PDF 1482 kb)

Supplementary Movie 1

This movie shows intravital imaging of WT and Nlrp10-/- dendritic cells in the skin. After an overnight stimulation with 1 μg/ml of LPS, 0.5 x 105 WT DCs labelled with CMTMR (Red) and 0.5 x 105 Nlrp10-/- DCs cells labelled with CFSE (Green) were mixed with an equal number of unlabelled WT and Nlrp10-/- DCs and co-injected intradermally with LPS into the ears of WT mice. Intravital two-photon laser scanning microscopy was performed four hours later. A blue emission resulting from second harmonic generation of collagen fibres highlights the epidermal junction. Images of skin adjacent to the injection site were collected every 30 seconds over the course of 60 minutes. The rendered movie represents a maximum intensity projection of a stack of 15 optical sections of a 400 um field of view. Movie is representative of three independent experiments. (MOV 4592 kb)

Supplementary Movie 2

This movie shows intravital microscopy of WT and Nlrp10-/- dendritic cells in the skin. After an overnight stimulation with 1 μg/ml of LPS, 1 x 105 WT DCs labelled with CMTMR (Red) and 1 x 105 Nlrp10-/- DCs cells labelled with CFSE (Green) were co-injected intradermally with LPS into the ears of WT mice and imaged as in Movie 1 four hours later. Images were collected every 30 seconds over the course of 80 minutes and the rendered movie represents a maximum intensity projection of a stack of 15 optical sections digitally zoomed to a 350 um field of view. Importantly, swapping the dye label between the WT and Nlrp10-/- DCs did not affect the results obtained by 2-photon microscopy (data not shown). (MOV 6740 kb)

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Eisenbarth, S., Williams, A., Colegio, O. et al. NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484, 510–513 (2012). https://doi.org/10.1038/nature11012

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