Identification of Clec4b as a novel regulator of bystander activation of auto-reactive T cells and autoimmune disease
Autoři:
Liselotte Bäckdahl aff001; Mike Aoun aff001; Ulrika Norin aff001; Rikard Holmdahl aff001
Působiště autorů:
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
aff001; The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an, China
aff002
Vyšlo v časopise:
Identification of Clec4b as a novel regulator of bystander activation of auto-reactive T cells and autoimmune disease. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008788
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008788
Souhrn
The control of chronic inflammation is dependent on the possibility of limiting bystander activation of autoreactive and potentially pathogenic T cells. We have identified a non-sense loss of function single nucleotide polymorphism in the C-type lectin receptor, Clec4b, and have shown that it controls chronic autoimmune arthritis in rat models of rheumatoid arthritis. Clec4b is specifically expressed in CD4+ myeloid cells, mainly classical dendritic cells (DCs), and is defined by the markers CD4+/MHCIIhi/CD11b/c+. We found that Clec4b limited the activation of arthritogenic CD4+αβT cells and the absence of Clec4b allowed development of arthritis already 5 days after adjuvant injection. Clec4b sufficient CD4+ myeloid dendritic cells successfully limited the arthritogenic T cell expansion immediately after activation both in vitro and in vivo. We conclude that Clec4b expressed on CD4+ myeloid dendritic cells regulate the expansion of auto-reactive and potentially pathogenic T cells during an immune response, demonstrating an early checkpoint control mechanism to avoid autoimmunity leading to chronic inflammation.
Klíčová slova:
Arthritis – Dendritic cells – Gene expression – Immune response – Intradermal injections – Oils – Spleen – T cells
Zdroje
1. Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. Nature Publishing Group, a division of Macmillan Publishers Limited. 2017 Jul;18(7):716–724. doi: 10.1038/ni.3731 28632714
2. Floreani A, Leung PSC, Gershwin ME. Environmental Basis of Autoimmunity. Clin Rev Allergy Immunol. Springer US; 2016 Jun;50(3):287–300. doi: 10.1007/s12016-015-8493-8 25998909
3. Kollias G, Papadaki P, Apparailly F, Vervoordeldonk MJ, Holmdahl R, Baumans V, et al. Animal models for arthritis: innovative tools for prevention and treatment. Ann Rheum Dis. BMJ Publishing Group Ltd; 2011 Aug;70(8):1357–62. doi: 10.1136/ard.2010.148551 21628308
4. Hoffmann MH, Bruns H, Bäckdahl L, Neregård P, Niederreiter B, Herrmann M, et al. The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis. 2013 Jul;72(7):1239–48. doi: 10.1136/annrheumdis-2012-202218 23172753
5. Vingsbo C, Sahlstrand P, Brun JG, Jonsson R, Saxne T, Holmdahl R. Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am J Pathol. American Society for Investigative Pathology; 1996 Nov;149(5):1675–83. 8909256
6. Bäckdahl L, Ekman D, Jagodic M, Olsson T, Holmdahl R. Identification of candidate risk gene variations by whole-genome sequence analysis of four rat strains commonly used in inflammation research. BMC Genomics. 2014;15(1):391–2.
7. Lorentzen JC, Glaser A, Jacobsson L, Galli J, Fakhrai-rad H, Klareskog L, et al. Identification of rat susceptibility loci for adjuvant-oil-induced arthritis. Proc Natl Acad Sci USA. 1998 May 26;95(11):6383–7. doi: 10.1073/pnas.95.11.6383 9600974
8. Vingsbo-Lundberg C, Nordquist N, Olofsson P, Sundvall M, Saxne T, Pettersson U, et al. Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats. Nat Genet. 1998 Dec;20(4):401–4. doi: 10.1038/3887 9843218
9. Griffiths MM, Wang J, Joe B, Dracheva S, Kawahito Y, Shepard JS, et al. Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis. Arthritis Rheum. 2000 Jun;43(6):1278–89. doi: 10.1002/1529-0131(200006)43:6<1278::AID-ANR10>3.0.CO;2-S 10857786
10. Ribbhammar U, Flornes L, Bäckdahl L, Luthman H, Fossum S, Lorentzen JC. High resolution mapping of an arthritis susceptibility locus on rat chromosome 4, and characterization of regulated phenotypes. Hum Mol Genet. 2003 Sep 1;12(17):2087–96. doi: 10.1093/hmg/ddg224 12915467
11. Rintisch C, Kelkka T, Norin U, Lorentzen JC, Olofsson P, Holmdahl R. Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus. Genes Immun. 2010 Apr;11(3):239–45. doi: 10.1038/gene.2010.2 20200546
12. Meyer-Wentrup F, Benitez-Ribas D, Tacken PJ, Punt CJA, Figdor CG, de Vries IJM, et al. Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-alpha production. Blood. American Society of Hematology; 2008 Apr 15;111(8):4245–53.
13. Kaden SA, Kurig S, Vasters K, Hofmann K, Zaenker KS, Schmitz J, et al. Enhanced dendritic cell-induced immune responses mediated by the novel C-type lectin receptor mDCAR1. The Journal of Immunology. 2009 Oct 15;183(8):5069–78. doi: 10.4049/jimmunol.0900908 19786536
14. Uto T, Fukaya T, Takagi H, Arimura K, Nakamura T, Kojima N, et al. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity. Nat Commun. 2016;7:11273. doi: 10.1038/ncomms11273 27068492
15. Lorentzen JC, Flornes L, Eklöw C, Bäckdahl L, Ribbhammar U, Guo JP, et al. Association of arthritis with a gene complex encoding C-type lectin-like receptors. Arthritis Rheum. 2007 Aug;56(8):2620–32. doi: 10.1002/art.22813 17665455
16. Richardson MB, Williams SJ. MCL and Mincle: C-Type Lectin Receptors That Sense Damaged Self and Pathogen-Associated Molecular Patterns. Front Immunol. Frontiers; 2014;5(22):288.
17. Hubert FX, Voisine C, Louvet C, Heslan M, Josien R. Rat Plasmacytoid Dendritic Cells Are an Abundant Subset of MHC Class II+ CD4+CD11b-OX62- and Type I IFN-Producing Cells That Exhibit Selective Expression of Toll-Like Receptors 7 and 9 and Strong Responsiveness to CpG. The Journal of Immunology. 2004 Jun 8;172(12):7485–94. doi: 10.4049/jimmunol.172.12.7485 15187127
18. Daws MR, Nakken B, Lobato-Pascual A, Josien R, Dissen E, Fossum S. Dendritic Cell Activating Receptor 1 (DCAR1) Associates With FcεRIγ and Is Expressed by Myeloid Cell Subsets in the Rat. Front Immunol. Frontiers; 2019;10:1060.
19. Colonna M, Trinchieri G, Liu Y-J. Plasmacytoid dendritic cells in immunity. Nat Immunol. Nature Publishing Group; 2004 Dec;5(12):1219–26. doi: 10.1038/ni1141 15549123
20. Alcántara-Hernández M, Leylek R, Wagar LE, Engleman EG, Keler T, Marinkovich MP, et al. High-Dimensional Phenotypic Mapping of Human Dendritic Cells Reveals Interindividual Variation and Tissue Specialization. Immunity. 2017 Dec 19;47(6):1037–1050.e6. doi: 10.1016/j.immuni.2017.11.001 29221729
21. Hubert FX, Voisine C, Louvet C, Heslan JM, Ouabed A, Heslan M, et al. Differential Pattern Recognition Receptor Expression but Stereotyped Responsiveness in Rat Spleen Dendritic Cell Subsets. J Immunol. 2006 Jul 3;177(2):1007–16. doi: 10.4049/jimmunol.177.2.1007 16818757
22. Voisine C, Hubert FX, Trinite B, Heslan M, Josien R. Two Phenotypically Distinct Subsets of Spleen Dendritic Cells in Rats Exhibit Different Cytokine Production and T Cell Stimulatory Activity. The Journal of Immunology. 2002 Sep 1;169(5):2284–91. doi: 10.4049/jimmunol.169.5.2284 12193693
23. Holmberg J, Tuncel J, Yamada H, Lu S, Olofsson P, Holmdahl R. Pristane, a non-antigenic adjuvant, induces MHC class II-restricted, arthritogenic T cells in the rat. J Immunol. 2006 Jan 15;176(2):1172–9. doi: 10.4049/jimmunol.176.2.1172 16394006
24. Turnbull E, MacPherson G. Immunobiology of dendritic cells in the rat. Immunol Rev. 2001 Dec;184:58–68. doi: 10.1034/j.1600-065x.2001.1840106.x 12086321
25. Bousso P. T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol. 2008 Sep;8(9):675–84. doi: 10.1038/nri2379 19172690
26. Muth S, Schütze K, Schild H, Probst HC. Release of dendritic cells from cognate CD4+ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity. Proc Natl Acad Sci USA. 2012 Jun 5;109(23):9059–64. doi: 10.1073/pnas.1110620109 22615402
27. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol. 2006 Jun;6(6):476–83. doi: 10.1038/nri1845 16691244
28. Liu GY, Fairchild PJ, Smith RM, Prowle JR, Kioussis D, Wraith DC. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity. 1995 Oct;3(4):407–15. doi: 10.1016/1074-7613(95)90170-1 7584132
29. Bäcklund J, Carlsen S, Höger T, Holm B, Fugger L, Kihlberg J, et al. Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis. Proc Natl Acad Sci USA. National Acad Sciences; 2002 Jul 23;99(15):9960–5. doi: 10.1073/pnas.132254199 12089323
30. Legge KL, Gregg RK, Maldonado-Lopez R, Li L, Caprio JC, Moser M, et al. On the Role of Dendritic Cells in Peripheral T Cell Tolerance and Modulation of Autoimmunity. J Exp Med. 2002 Jul 15;196(2):217–27. doi: 10.1084/jem.20011061 12119346
31. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med. 2001 Sep 17;194(6):769–79. doi: 10.1084/jem.194.6.769 11560993
32. Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med. 2002 Dec 16;196(12):1627–38. doi: 10.1084/jem.20021598 12486105
33. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, et al. Differential antigen processing by dendritic cell subsets in vivo. Science. 2007 Jan 5;315(5808):107–11. doi: 10.1126/science.1136080 17204652
34. Price JD, Hotta-Iwamura C, Zhao Y, Beauchamp NM, Tarbell KV. DCIR2 +cDC2 DCs and Zbtb32 Restore CD4 +T-Cell Tolerance and Inhibit Diabetes. Diabetes. 2015 Sep 24;64(10):3521–31. doi: 10.2337/db14-1880 26070317
35. Sung SSJ, Bolton WK. Editorial: Are men rats? Dendritic cells in autoimmune glomerulonephritis. J Leukoc Biol. 2010 Nov 1;88(5):831–5. doi: 10.1189/jlb.0610356 21041514
36. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, et al. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med. 2001 Dec 17;194(12):1823–34. doi: 10.1084/jem.194.12.1823 11748283
37. Yu H, Zhang P, Yin X, Yin Z, Shi Q, Cui Y, et al. Human BDCA2+CD123+CD56+ dendritic cells (DCs) related to blastic plasmacytoid dendritic cell neoplasm represent a unique myeloid DC subset. Protein Cell. 2015 Mar 18;6(4):297–306. doi: 10.1007/s13238-015-0140-x 25779340
38. Holmdahl R, Carlsen S, Mikulowska A Vestberg M, Brunsberg U, Hansson A, et al. Genetic analysis of mouse models for Rheumatoid Arthritis In: Kenneth WA, editor. Human Genome Methods. New York: CRC press (1998)p. 215–238.
39. Tuncel J, Haag S, Hoffmann MH, Yau ACY, Hultqvist M, Olofsson P, et al. Animal Models of Rheumatoid Arthritis(I): Pristane-Induced Arthritis in the Rat. PLoS ONE. 2016;11(5):e0155936. doi: 10.1371/journal.pone.0155936 27227821
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 6
- Prof. Libor Grubhoffer: Nová varianta mpox je příležitostí pokročit v poznání původce varioly
- Co obsahují nové pokyny WHO pro dozor nad antibiotickou rezistencí?
- AI místo lékaře? Výzkum zkoumal ochotu Čechů konzultovat své zdraví s umělou inteligencí
- Prof. Jan Škrha: Metformin je bezpečný, ale je třeba jej bezpečně užívat a léčbu kontrolovat
- Ibuprofen jako alternativa antibiotik při léčbě infekcí močových cest
Nejčtenější v tomto čísle
- AXR1 affects DNA methylation independently of its role in regulating meiotic crossover localization
- Osteocalcin promotes bone mineralization but is not a hormone
- Super-resolution imaging of RAD51 and DMC1 in DNA repair foci reveals dynamic distribution patterns in meiotic prophase
- Reciprocal regulation between nicotinamide adenine dinucleotide metabolism and abscisic acid and stress response pathways in Arabidopsis