Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

C9orf72 in myeloid cells suppresses STING-induced inflammation

Nature volume 585, pages 96–101 (2020)Cite this article

Subjects

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1,2,3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4,5,6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72−/− mice show marked early activation of the type I interferon response, and C9orf72−/− myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein—a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72−/− myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72−/− immune cells as well as splenomegaly and inflammation in C9orf72−/− mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: DC development and T-cell activation in young and aged C9orf72−/− mice.
Fig. 2: Loss of C9orf72 in myeloid cells drives increased production of type I interferons through STING.
Fig. 3: C9orf72−/− mice are more susceptible to EAE and have increased antitumour immunity compared with wild-type mice.
Fig. 4: Patients with C9orf72 repeat expansion in ALS have an enhanced type I interferon signature in peripheral myeloid cells that can be suppressed by a STING antagonist.

Similar content being viewed by others

Data availability

The RNA sequencing data reported here have been deposited in Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov) under accession number GSE151936. Data from GSE151936 were used for Figs. 1h, i, 2k, 4a, b, i and Extended Data Figs. 4a, b, 5a, b, 6a–g, 7c and 8a–f. Human whole-blood RNA sequencing data reported here can be accessed from the database of Genotypes and Phenotypes (dbGaP, https://www.ncbi.nlm.nih.gov/gap) using accession number phs002055.v1.p1. Data from dbGaP with accession number phs002055.v1.p1 were used for Fig. 4d, e. Human cerebellum RNA-seq data can be found in ref. 30. Source data are provided with this paper.

References

  1. Turner, M. R., Goldacre, R., Ramagopalan, S., Talbot, K. & Goldacre, M. J. Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. Neurology 81, 1222–1225 (2013).

    Article  CAS  Google Scholar 

  2. Miller, Z. A. et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J. Neurol. Neurosurg. Psychiatry 84, 956–962 (2013).

    Article  Google Scholar 

  3. Miller, Z. A. et al. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: completing the picture. Neurol. Neuroimmunol. Neuroinflamm. 3, e301 (2016).

    Article  Google Scholar 

  4. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    Article  CAS  Google Scholar 

  5. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

    Article  CAS  Google Scholar 

  6. Belzil, V. V. et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 126, 895–905 (2013).

    Article  CAS  Google Scholar 

  7. O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

    Article  ADS  Google Scholar 

  8. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).

    Article  CAS  ADS  Google Scholar 

  9. Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347ra93 (2016).

    Article  Google Scholar 

  10. Ganguly, D., Haak, S., Sisirak, V. & Reizis, B. The role of dendritic cells in autoimmunity. Nat. Rev. Immunol. 13, 566–577 (2013).

    Article  CAS  Google Scholar 

  11. Gardner, A. & Ruffell, B. Dendritic cells and cancer immunity. Trends Immunol. 37, 855–865 (2016).

    Article  CAS  Google Scholar 

  12. Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438 (2015).

    Article  CAS  Google Scholar 

  13. Abram, C. L., Roberge, G. L., Hu, Y. & Lowell, C. A. Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J. Immunol. Methods 408, 89–100 (2014).

    Article  CAS  Google Scholar 

  14. Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013).

    Article  CAS  Google Scholar 

  15. Konno, H., Konno, K. & Barber, G. N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155, 688–698 (2013)

    Article  CAS  Google Scholar 

  16. Gonugunta, V. K. et al. Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. 21, 3234–3242 (2017).

    Article  CAS  Google Scholar 

  17. Prabakaran, T. et al. Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J. 37, e97858 (2018).

    Article  Google Scholar 

  18. Nassif, M., Woehlbier, U. & Manque, P. A. The enigmatic role of C9ORF72 in autophagy. Front. Neurosci. 11, 442 (2017).

    Article  Google Scholar 

  19. Gui, X. et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567, 262–266 (2019).

    Article  CAS  ADS  Google Scholar 

  20. Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).

    Article  CAS  ADS  Google Scholar 

  21. Sharma, S. et al. Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc. Natl Acad. Sci. USA 112, E710–E717 (2015).

    Article  CAS  Google Scholar 

  22. McAlpine, W. et al. Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. Proc. Natl Acad. Sci. USA 115, E11523–E11531 (2018).

    Article  CAS  Google Scholar 

  23. Huber, J. P. & Farrar, J. D. Regulation of effector and memory T-cell functions by type I interferon. Immunology 132, 466–474 (2011).

    Article  CAS  Google Scholar 

  24. Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120–131 (2012).

    Article  CAS  Google Scholar 

  25. O’Connor, R. A. et al. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. 181, 3750–3754 (2008).

    Article  Google Scholar 

  26. Ismail, A. et al. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. J. Neurol. Neurosurg. Psychiatry 84, 79–87 (2013).

    Article  Google Scholar 

  27. Lemos, H. et al. Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J. Immunol. 192, 5571–5578 (2014).

    Article  CAS  Google Scholar 

  28. Gibson, S. B. et al. Population-based risks for cancer in patients with ALS. Neurology 87, 289–294 (2016).

    Article  Google Scholar 

  29. Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014); erratum 42, 199 (2015).

    Article  CAS  Google Scholar 

  30. Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci. 18, 1175–1182 (2015).

    Article  CAS  Google Scholar 

  31. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    Article  CAS  ADS  Google Scholar 

  32. Xiao, Y. et al. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J. Exp. Med. 214, 1493–1507 (2017).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Jeroen Pasterkamp for providing C9orf72fl/fl mice; M. Vasquez for maintaining the animal colony; H. Maghzi for assisting with EAE experiments; G. Martins for running the flow cytometry core; and and M. Maniex for assistance with tissue collection. A.Y. is the recipient of a Ramón y Cajal fellowship from the Ministerio de Ciencia, Innovación y Universidades, Spain. This work was supported by NIH grant NS069669 (to R.H.B), the Robert and Louise Schwab family, the Cedars-Sinai ALS Research Fund (to R.H.B.), Arthritis Foundation grant AF2017-433570 (to C.J), and NIH grant 1R21AI126368-01 (to M.A.).

Author information

Authors and Affiliations

  1. Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Madelyn E. McCauley, Jacqueline Gire O’Rourke, Deepti Lall, A. K. M. G. Muhammad, Shaughn Bell, Jesse Landeros, Viviana Valencia & Robert H. Baloh

  2. Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Madelyn E. McCauley, Jacqueline Gire O’Rourke, Ritchie Ho, Deepti Lall, A. K. M. G. Muhammad, Shaughn Bell & Robert H. Baloh

  3. Departament de Microbiologia i Ecologia, Universitat de València, Burjassot, Spain

    Alberto Yáñez

  4. Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universitat de València, Burjassot, Spain

    Alberto Yáñez

  5. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Janet L. Markman, Shuang Chen, Mengyao Jin, Moshe Arditi & Caroline Jefferies

  6. Institute for Genomic Medicine, Columbia University, New York, NY, USA

    Xinchen Wang & Matthew Harms

  7. Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Mengyao Jin & Caroline Jefferies

  8. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Robert H. Baloh

Authors
  1. Madelyn E. McCauley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacqueline Gire O’Rourke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Yáñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janet L. Markman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ritchie Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinchen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shuang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Deepti Lall
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mengyao Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. K. M. G. Muhammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shaughn Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jesse Landeros
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Viviana Valencia
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Matthew Harms
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Moshe Arditi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Caroline Jefferies
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Robert H. Baloh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.E.M. coordinated the project and was involved in all experiments as well as data collection and statistical analysis. J.G.O., J.L. and M.E.M. were involved in EAE experiments. M.E.M. and A.Y. performed flow cytometry. J.G.O., V.V. and M.E.M. were involved in BMDM, PBMC and MDM experiments and analysis. V.V. and J.G.O. performed western blots. J.L.M., S.C. and M.A. were involved in B16 melanoma experiments and analysis. A.K.M.G.M. performed haematoxylin and eosin (H&E) and luxol fast blue (LFB) staining. D.L. performed microglia experiments and analysis. J.L. established and maintained mouse colonies. M.J. assisted with STING stimulation assays. A.K.M.G.M., J.G.O. and M.E.M. carried out tissue collection and analysis. S.B., R.H., X.W. and M.H. analysed RNA-seq data. M.E.M., C.J. and R.H.B. planned, designed and interpreted the experiments. M.E.M. and R.H.B. wrote the manuscript.

Corresponding author

Correspondence to Robert H. Baloh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Tony Wyss-Coray, Aaron D. Gitler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 DCs and T cells develop normally in C9orf72−/− mice, but markers of immune activation and inflammatory cytokine production are seen from a young age.

a, Percentage of DC populations in total splenocytes of 8-week-old mice (n = 5). b, MFI measured via flow cytometry for MHC class II and costimulatory molecules (CD80, CD86 and CD40) of three splenic DC populations (CD11b, CD8a and pDC) from 8-week-old mice (n = 5). c, Percentage of DC populations from total splenocytes of 8-month-old mice (n = 6). d, MFI measured via flow cytometry for MHC II and costimulatory molecules of splenic DC populations from 8-month-old mice (n = 6). e, Intracellular TNF staining of splenic DCs from 10-week-old mice after stimulation with LPS (100 ng ml−1) (n = 3). f, Quantification of double-negative (DN), double-positive (DP) and single-positive CD4 and CD8 T-cell populations in the thymus of 8-week-old mice (n = 3). g, Percentage of Foxp3+ CD4 T cells in the spleen of 8-week-old mice (n = 3), showing no change in T-regulatory cell populations. h, ELISA of supernatants collected from isolated CD4 T cells from the spleen of 6-month-old mice after anti-CD3/anti-CD28 treatment for 72 h. Graphs show a representative experiment with biological replicates, which was repeated twice. a–h, One-way ANOVA. e, i, Data shown as means ± s.e.m. h, Data shown as means ± s.d.

Source data

Extended Data Fig. 2 Profiling of splenocytes from myeloid-specific deletion of C9orf72 via Cx3cr1Cre.

a, Proportions of immune-cell populations in 12-month-old C9orf72fl/fl:Cx3cr1Cre mice. iMono, inflammatory monocytes; Macs, macrophages; Neut., neutrophils; pMono, patrolling monocytes. b, Proportions of splenic DC populations in 5-month-old C9orf72fl/fl:Cx3cr1Cre mice (n = 7). c, C9orf72fl/fl;Cx3cr1Cre CD11b splenic DCs from 5-month-old mice have increased MFI for CD86 compared with C9orf72fl/fl mice (n = 4). d, MFI for splenic DC MHC II and costimulatory molecules in 5-month-old C9orf72fl/fl:Cx3cr1Cre mice (n = 7). Unpaired two-tailed Student’s t-test. b, c, Data shown as means ± s.e.m.

Source data

Extended Data Fig. 3 Immune profiling of C9orf72fl/fl:LysMCre mice.

a, Left, gross images of splenomegaly in C9orf72fl/fl:LysMCre mice. Right, spleen weights from C9orf72fl/fl and C9orf72fl/fl;LysMCre mice (in milligrams) normalized to body weight (in grams) at 5 months (n = 4). b, Proportions of splenic DC populations in 5-month-old C9orf72fl/fl;LysMCre mice (n = 4). c, Proportions of splenic DC populations in 12-month-old C9orf72fl/fl;LysMCre mice (n = 4). d, MFI of splenic DC MHC II and costimulatory molecules in 5-month-old C9orf72fl/fl;LysMCre mice (n = 4). e, MFI measured via flow cytometry for MHC II and costimulatory molecules of splenic DC populations from 12-month-old C9orf72fl/fl;LysMCre mice (n = 4). f, Percentages of CD4 and CD8 T cells in splenocytes. g, h, CD4 T cell (g) and CD8 T cell (h) activation states in 5-month-old C9orf72fl/fl;LysMCre mice. i, Percentages of CD4 and CD8 T cells amongst splenocytes in 12-month-old mice. j, k, CD4 T cell (j) and CD8 T cell (k) activation states in 12-month-old C9orf72fl/fl;LysMCre mice (n = 4). Unpaired two-tailed Student’s t-test. a–c, Data shown as means ± s.e.m.

Source data

Extended Data Fig. 4 RNA-seq values for genes stimulated by type I interferon in different immune populations following total-body versus myeloid-cell-specific deletion of C9orf72.

a, b, RNA-seq of CD11b cells (a) and B cells (b) from wild-type (WT; n = 4), total knockout (C9(−/−); n = 3) and C9orf72fl/fl;Cx3cr1Cre (n = 4) mice. The results are similar to those observed in DCs of total-body nulls (Fig. 2), and show activation of ISGs. Results from T cells of the same dataset are shown in Fig. 1. Two-way ANOVA; data shown as means ± s.e.m.

Extended Data Fig. 5 RNA-seq of C9orf72-deficient DCs, responses of ISGs in BMDMs to TLR agonists, and amelioration of type I interferon responses by deletion of STING.

a, PCA plot from RNA-seq of freshly isolated splenic classical DCs from 10-week-old mice (n = 4). b, TPM values for the indicated cytokines and inflammatory genes (WT, n = 4; C9(−/−), n = 4 biologically independent samples). c–e, qRT–PCR analysis of Ifnb1, Mx1 and Cxcl10 in WT and C9(−/−) BMDMs after stimulation with CpG (c), poly I:C (d) and LPS (e) (representative of three experiments). f, The STING antagonist H151 blocks the hyperactive ISG response to stimulation with cGAMP (representative of three experiments). g, qRT–PCR analysis of IFNβ in total BMDMs of WT, Gt(−/−), C9(−/−) and C9(−/−):Gt(−/−) mice after stimulation with cGAMP. Representative of three independent experiments. b–e, Unpaired two-tailed t-test. f, g, One-way ANOVA. b, Data shown as means ± s.e.m. c–g, Data shown as means ± s.d.

Source data

Extended Data Fig. 6 Deletion of STING mitigates the increased gene-expression response to type I interferon in C9orf72−/− immune cells.

a–d, Heat maps showing ISGs from RNA-seq of isolated splenocyte populations from 3-month-old mice. Cell types are indicated and include: a, CD11b myeloid cells; b, CD4 T cells; c, CD8 T cells; d, B cells, from WT, C9(−/−) and C9orf72;STING double knockout (C9(−/−)/Gt(−/−)) mice. e–g, TPM values of indicated ISGs in: e, CD4 T cells (WT, n = 4; C9(−/−), n = 3; C9(−/−)/Gt(−/−), n = 4); f, CD8 T cells (WT, n = 4; C9(−/−), n = 3; C9(−/−)/Gt(−/−), n = 4); and g, B cells (WT, n = 4; C9(−/−), n = 3; C9(−/−)/Gt(−/−), n = 4). Deletion of STING leads to a marked rescue of ISG expression across all cell types. e–g, Two-way ANOVA; data shown as means ± s.e.m.

Extended Data Fig. 7 Activation markers of splenocyte populations in WT, C9(−/−) and Gt(−/−) mice.

a, b, Results from flow cytometry analysis of splenic CD11c costimulatory markers in 3-month-old WT (n = 4), C9(−/−) (n = 5) and C9(−/−)/Gt(−/−) (n = 4) mice. c, RNA-seq results for splenic CD11b cells from 3-month-old WT (n = 4), C9(−/−) (n = 3) and C9(−/−)/Gt(−/−) (n = 4) mice. d, e, Results from flow cytometry analysis of splenic CD4 T cells (d) and CD8 T cells (e) from 3-month-old mice. One-way ANOVA. a, b, d, e, Data shown as means ± s.e.m.

Source data

Extended Data Fig. 8 C9orf72−/− T cells show increased activation and markers of TH1 polarization.

a–c, Heat map from RNA-seq data for isolated CD4 T cells (a), CD8 T cells (b) and B cells (c) from spleens of 3-month-old WT (n = 4) and C9(−/−) (n = 3) mice. d–f, Markers of TH1 (d), TH2 (e) and TH17 (f) polarization genes from CD4 T cells. Two-way ANOVA. d–f, Data shown as means ± s.e.m.

Extended Data Fig. 9 C9orf72−/− mice are more susceptible than wild-type mice to EAE and show increased infiltration of TH1-polarized T cells into nervous tissue.

a, Representative LFB staining of spinal cord from WT (n = 3), C9(+/−)(n = 3) and C9(−/−) (n = 3) mice. b, Representative H&E staining of spinal cords from WT (n = 3), C9(+/−) (n = 3) and C9(−/−) (n = 3) mice at end stage. c, IBA1 staining of spinal cord from the indicated genotypes (n = 3). d, e, Splenic C9(−/−) CD4 (d) and CD8 (e) T cells produce increased levels of IFNγ during pre-onset (day 9) (WT, n = 4; C9(+/−), n = 4; C9(−/−), n = 3 biologically independent samples) and peak (day 15) (WT, n = 3; C9(+/−), n = 3; C9(−/−), n = 3 biologically independent samples) of EAE. f–i, Total number of CD3+ T cells (f), IFNγ+ CD4 T cells (g), IL-17+ CD4 T cells (h) and IFNγ+ IL-17+ CD4 T cells (i) in whole brain of WT (n = 2), C9(+/−) (n = 3) and C9(−/−) (n = 3) mice during the peak (day 15) of disease. f–i, One-way ANOVA; data shown as means ± s.e.m.

Source data

Extended Data Fig. 10 C9orf72−/− mice that are resistant to B16 melanoma tumours show an enhanced cytotoxic T cell response.

a, Percentages of CD44+ CD4 T cells (left) and CD8 T cells (right) in the lungs of WT (n = 2), C9(+/−) (n = 3) and C9(−/−) (n = 3) mice on day 14 of B16 melanoma challenge. b, c, Percentages of naive CD4 T cells (b) and memory CD4 T cells (c) in the spleens of WT, C9(+/−) and C9(−/−) mice with and without inoculation with B16 cells (n = 5). d–f, Percentages of naive CD8 T cells (d), memory CD8 T cells (e) and effector memory CD8 T cells (f) in the spleens of WT, C9(+/−) and C9(−/−) mice with and without inoculation with B16 cells (n = 5). One-way ANOVA; data shown as means ± s.e.m.

Source data

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3.

Reporting Summary

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCauley, M.E., O’Rourke, J.G., Yáñez, A. et al. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature 585, 96–101 (2020). https://doi.org/10.1038/s41586-020-2625-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-020-2625-x

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing