Abstract
Aberrant differentiation of progenitor cells in the hematopoietic system is known to severely impact host immune responsiveness. Here we demonstrate that NOD1, a cytosolic innate sensor of bacterial peptidoglycan, also functions in murine hematopoietic cells as a major regulator of both the generation and differentiation of lymphoid progenitors as well as peripheral T lymphocyte homeostasis. We further show that NOD1 mediates these functions by facilitating STAT5 signaling downstream of hematopoietic cytokines. In steady-state, loss of NOD1 resulted in a modest but significant decrease in numbers of mature T, B and natural killer cells. During systemic protozoan infection this defect was markedly enhanced, leading to host mortality. Lack of functional NOD1 also impaired T cell-dependent anti-tumor immunity while preventing colitis. These findings reveal that, in addition to its classical role as a bacterial ligand receptor, NOD1 plays an important function in regulating adaptive immunity through interaction with a major host cytokine signaling pathway.
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Data availability
Data supporting this study are included within the article and supporting materials. RNA-seq data in this manuscript have been deposited in the NCBI Gene Expression Omnibus (GEO) and are accessible through accession number GSE236485. Source data are provided with this paper.
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Acknowledgements
We thank D. G. Kugler and K. Shenderov for contributing initial observations on ΔCARD NOD1 mice and S. Oland, L. Mittereder and S. Hieny for excellent technical assistance. We also thank C. Eigsti, T. Hawley, M. Suzuki, M. Zhao and L. Olano (NIAID Research Technology Branch) for FACS sorting and mass spectrometry analyses, as well as C. Liu (National Heart, Lung and Blood Institute) for generating the CRISPR NOD1−/− animals. We thank N. Riteau and M. Moayeri for discussions and help with western blotting and C. H. Iwamura for advice on analysis of bone marrow precursors. We thank R. Carvalho and D. Zamboni (University of San Paolo, Brazil) for determining splenocyte cellularity in their colony of NOD1−/− mice and M. Divangahi (McGill University, Montreal, Canada) for providing lymphoid tissues from his colony of NOD1−/− animals as well as for critical reading of the manuscript. Our NOD1−/− colony was derived from mice originally generated by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and provided by W. Strober (NIAID). ΔCARD NOD1 mice were provided by T. J. Merkel (Center for Biologics Evaluation/US Food and Drug Administration), while J.-H. Park (National Cancer Institute) supplied the IL-7Tg animals. Finally, we thank M. Lenardo (NIAID) for his comments on the manuscript. This work utilized the computational resources of the NIH HPC Biowulf cluster and was supported by the Intramural Research Program of the NIAID and by a fellowship from the Uehara Memorial Foundation (C.I.).
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C.I. and D.J. conceived and designed the study. C.I. conducted experiments and acquired and analyzed data with help from D.J. H.O. performed PLA. F.A.F. and A.C. helped with OP9 and WB experiments, respectively. L.Z. contributed plasmid constructs. Y.M., Y.K. and S.R.B. generated and analyzed the RNA-seq data. H.W. helped with key suggestions. G.T., R.E.G., J.J.O., T.N. and A.S. provided resources. C.I., A.S. and D.J. wrote the manuscript and all authors provided feedback.
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Nature Immunology thanks Michael Farrar and Seth Masters for their contribution to the peer review of this work. L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Extended data
Extended Data Fig. 1 NOD1−/− mice do not express NOD1 mRNA while ΔCARD NOD1 animals synthesize a truncated transcript lacking exons 2 and 3 encoding the CARD domain.
a, Schematic diagram of regions amplified by 6 primer sets (# 1-6) used to detect mRNA corresponding to exons 1, 2, 3, 4, 6-7 and 12 of Nod1. b, Expression of Nod1 mRNA in dendritic cells derived from WT, NOD1−/− or ΔCARD NOD1 bone marrow cells measured using all six primer sets indicated in a. Bars represent mean ± S.D. of qRT-PCR triplicates for Nod1 mRNA expression relative to Hprt measured from one representative out of three experiments performed using in vitro derived dendritic cells from pools of BM cells from at least 2 animals per group. AU, arbitrary units. c, Representative alignment of RNA-seq measurements for Nod1 in Linneg BM cells from WT, NOD1−/− and ΔCARD NOD1 mice. The same result was obtained when RNA-seq was performed on CD4+ T cells from the three groups of mice (data not shown). The insert indicates the enlarged region between exons 2 and 4. d, Schematic diagram of genomic DNA and cDNA for Nod1 gene in the ΔCARD NOD1 mouse based on the data obtained after sequencing cDNA (Supplementary Data Fig. 1).
Extended Data Fig. 2 NOD1 expression in hematopoietic but not radio-resistant cells is required for optimal lymphopoiesis.
a, Schematic diagram of the bone marrow reconstitution experiment performed (left).The total number of CD45.1+ cells in spleen, thymus and bone marrow and in the indicated populations analyzed in parallel from irradiated CD45.2+ WT, NOD1−/− or ΔCARD NOD1 recipient mice (n = 5-6) reconstituted 8 weeks prior with the same preparation of WT CD45.1+ bone marrow cells (106/mouse). b–d, Schematic diagram of the bone marrow reconstitution experiments performed (top). Frequency of donor cells in bone marrow, thymus and spleen of irradiated CD45.1/2+ WT recipients reconstituted with a mixture of equal number of bone marrow cells from WT and NOD1−/− (b), WT and ΔCARD NOD1 (c) or NOD1−/− and ΔCARD NOD1 (d) mice expressing either CD45.1 or CD45.2 congenic marker. Each symbol represents a value obtained for an individual mouse and bars indicate the mean ± s.e.m. per genotype (n = 8–10) pooled from two independent experiments performed (a–d). Significant differences between groups were determined by two-sided Mann-Whitney test and indicated by asterisks. ***P < 0.001.
Extended Data Fig. 3 Lymphopenic status of NOD1−/− and ΔCARD NOD1 mice is not associated with gut microbiota composition.
a, Representative contour plots of thymus and spleen from CD45.1/2+ mice treated ad libitum with drinking water containing VANM antibiotic cocktail for 4 weeks before and 8 weeks after being irradiated and reconstituted with an equal number of BM cells from CD45.1+ ΔCARD NOD1 and CD45.2+ WT mice (n = 5). Statistical differences were determined by one-way ANOVA (Tukey’s multiple comparisons). ***P < 0.001. b, c, Three week old NOD1−/− (b) and ΔCARD NOD1 (c) were co-housed with age and gender matched WT animals for six weeks at which time the cellularity of different lymphoid organs was determined. (a-c) Each symbol depicts values obtained for an individual mice (n = 5). Bars represent the mean ± s.e.m of values from one representative out of two independent experiments performed. Statistical differences were determined by two-sided Mann-Whitney test.*P < 0.05, **P < 0.01, ***P < 0.001. d, Survival kinetics of co-housed WT (n = 9) and ΔCARD NOD1 (n = 12) mice infected i.p. with T. gondii ME-49 cysts. Significance was determined by Log-rank (Mantel-Cox) test.**P < 0.01. e, Stacked bar plot showing taxonomic relative abundance of fecal microbial communities at the family level in stool samples collected from WT (n = 9) and ΔCARD NOD1 (n = 11) mice before and after co-housing.
Extended Data Fig. 4 Rip2−/− mice do not display lymphopenia, decreased cytokine responsiveness or increased susceptibility to T. gondii infection.
a-b, Total cell number in spleen, thymus and BM (a) and number of LT-HSC, ST-HSC, CLP and CMP in BM (b) of age-matched WT and Rip2−/− animals (n = 6-9 and 4–6 in a and b, respectively). Each symbol represents values obtained for an individual mouse and bars indicate the mean value ± s.e.m. for each genotype pooled from two independent experiments performed. c, Proliferative response of FACS-purified LT-HSC (left) and CLP (right) stimulated with indicated hematopoietic cytokines was measured. Bars indicate mean ± S.D. values for at least duplicate cultures for one representative out of two performed. d, Survival kinetics of WT (n = 14), NOD1−/− (n = 4) or Rip2−/− (n = 10) mice infected i.p. with ME-49 cysts. Significance was determined by Log-rank (Mantel-Cox) test *P < 0.05, **P < 0.01.
Extended Data Fig. 5 Comparison of numbers of total splenocytes and splenic CD4 and CD8 T cells in mice with two WT, one WT one WT and ΔCARD NOD1 or two ΔCARD NOD1 alleles.
a, Schematic diagram of breeding strategy used to generate mice with only one WT or one WT and one ΔCARD NOD1 allele. Both crosses were performed in parallel. b, Bars represent the mean ± s.e.m. of cell numbers in indicated populations for WT (n = 9), NOD1−/− (n = 7), WT ΔCARD NOD1 heterozygote (n = 5) and ΔCARD NOD1 (n = 3) mice. Significant differences between groups were determined by two-sided Mann-Whitney test and indicated by asterisks. *P < 0.05, **P < 0.01, ***P < 0.001.
Extended Data Fig. 6 Increased numbers of NK and CD8+ T cells after in vivo administration of rIL-15 in NOD1−/− and ΔCARD NOD1 mice.
Number of splenocytes and indicated lymphocyte populations in spleens from WT, NOD1−/− or ΔCARD NOD1 control and mice implanted with mini-osmotic pumps releasing rIL-15 for two weeks. The analysis was performed one week after the treatment was stopped. Each symbol represents a value obtained for an individual mouse and bars indicate the mean ± s.e.m. in untreated (n = 7-11) or treated (n = 7-8) group pooled from two independently performed experiments. Significant differences between the groups were determined by two-sided Mann-Whitney test and indicated by asterisks *P < 0.05, **P < 0.01, ***P < 0.001.
Extended Data Fig. 7 Interaction of NOD1 and STAT5a in primary human NK cells and CD4+ T lymphocytes.
a, Interaction of NOD1, STAT5 and HSP90 in NK cells following stimulation with IL-15 was detected after cell lysis, immunoprecipitation with anti-STAT5a Ab, SDS-PAGE and western blot analysis with antibodies specific for STAT5a, NOD1, HSP90 and β-actin. b, Association of NOD1 and Rip2 protein, but not STAT5 in primary human monocytes stimulated with NOD1 ligand, evaluated by PLA and confocal microscopy. Representative images for unstimulated and stimulated cells (left) and quantification of PLA dots in cell (n = 40–281) (right) are shown. c, Evaluation of NOD1/STAT5a interaction in FACS sorted human primary CD4+ T lymphocytes following stimulation with or without rIL-7. Representative images for unstimulated and stimulated cells (left) and quantification of PLA dots in cell (n = 465–1433) (right) are shown. d, Association of NOD1 with STAT5 and HSP90 but not STAT3 in human primary CD4 T cells cells following stimulation with rIL-7 detected by PLA analysis. Representative images (left) and quantification of PLA dots in cell (n = 86–153) (right) are shown. (b-d) Arrows indicate positions of PLA dots. Scale bar: 5 μm. All violin plots are overlaid with white boxplot, while red line indicates mean value. Significant differences were determined by two-sided Mann-Whitney test. **P < 0.01, ***P < 0.001. (a-d) Data shown from one representative out of two experiments performed.
Extended Data Fig. 8 Impaired phosphorylation and nuclear translocation of STAT5 in IL-15-treated NOD1−/− and ΔCARD NOD1 naïve CD8+ T lymphocytes.
Naïve CD8+ T lymphocytes from WT, NOD1−/− and ΔCARD NOD1 mice were pretreated with or without rIL-15 (10 ng/ml) and cytosolic and nuclear fractions were probed with anti-STAT5 and anti-pSTAT5 Ab. Numbers indicate the intensity of STAT5 bands compared to tubulin or histone H3 protein controls for each cell compartment. Data shown from one representative out of two experiments performed.
Extended Data Fig. 9 Compromised T cell functions in ΔCARD NOD1 mice.
a–c, CD4+ T lymphocytes from ΔCARD NOD1 mice fail to induce colitis in an adoptive transfer model. (a) Kinetics of body weight (mean ± s.e.m.) loss after transfer of CD4+ T cells from WT or ΔCARD NOD1 mice into RAG−/− recipients (n = 5/group). (b) Histological score and representative photomicrographs of hematoxylin and eosin-stained sections of ileum from recipients on day 69 post-transfer (bar = 400 μm). (c) Number of donor T cells recovered at the same time point is shown as FACS contour plots for splenocytes from one representative mouse. Each symbol represents a value obtained for an individual mouse from a single experiment and bars depicts the mean ± s.e.m. values for a group. d–f, ΔCARD NOD1 animals display increased susceptibility to tumor challenge. (d) B16 tumors in WT or ΔCARD NOD1 animals and (e) representative photomicrographs of a hematoxylin and eosin-stained section of a tumor from each group (bar = 3 mm) on day 14 after injection. (f) Kinetics of tumor size in WT or ΔCARD NOD1 mice. Each symbol depicts a value obtained for an individual mouse (n = 8) pooled from two independent experiments performed. (g) Quantification of necrotic areas in tumors on day 14 post-injection (n = 5) from one of two experiments. Bars indicate the mean ± s.e.m. values. (b,c,f,g) Data were analyzed using a two-sided Mann-Whitney test. *P < 0.05, **P < 0.01.
Extended Data Fig. 10 Working model for NOD1-controlled STAT5-medaited lymphopoiesis.
The diagram depicts the proposed role of NOD1 in the STAT5 signaling pathway downstream of lymphopoietic cytokine receptors in the three different mouse genotypes studied here. In the case of WT mice (a) cytokine receptor engagement triggers phosphorylation and dimerization of STAT5, which are facilitated by NOD1, resulting in optimal STAT5 nuclear translocation followed by induction of lymphopoiesis. In mice lacking the entire NOD1 protein (b) STAT5 phosphorylation is decreased, fewer p-STAT5 dimers are formed, and although nuclear translocation is not affected, the STAT5-mediation signal is diminished. In mice that express ΔCARD NOD1 (c) both the STAT5 phosphorylation and its nuclear translocation are impaired, resulting in an even lower lymphopoietic cytokine output.
Supplementary information
Supplementary Information
cDNA sequence of truncated Nod1 gene (exons 1–12) in ΔCARD NOD1 mouse, gating strategy for FACS analysis, mass spectrometry results and list of primers.
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Iwamura, C., Ohnuki, H., Flomerfelt, F.A. et al. Microbial ligand-independent regulation of lymphopoiesis by NOD1. Nat Immunol 24, 2080–2090 (2023). https://doi.org/10.1038/s41590-023-01668-x
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DOI: https://doi.org/10.1038/s41590-023-01668-x
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