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

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).

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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.

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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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