Toll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation.
Adoptive Transfer
Animals
Antigen Presentation
Autoantigens
/ immunology
Cell Separation
Chemokines
/ immunology
Colitis
/ immunology
Dendritic Cells
/ immunology
Disease Models, Animal
Epithelial Cells
/ immunology
Flow Cytometry
Lipopolysaccharide Receptors
/ metabolism
Mice
Receptors, Immunologic
/ metabolism
Self Tolerance
Sequence Analysis, RNA
Signal Transduction
/ immunology
Single-Cell Analysis
T-Lymphocytes, Regulatory
/ immunology
Thymus Gland
/ cytology
Toll-Like Receptors
/ metabolism
Up-Regulation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 05 2020
12 05 2020
Historique:
received:
02
07
2019
accepted:
12
04
2020
entrez:
14
5
2020
pubmed:
14
5
2020
medline:
1
9
2020
Statut:
epublish
Résumé
The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14
Identifiants
pubmed: 32398640
doi: 10.1038/s41467-020-16081-3
pii: 10.1038/s41467-020-16081-3
pmc: PMC7217920
doi:
Substances chimiques
Autoantigens
0
Cd14 protein, mouse
0
Chemokines
0
Lipopolysaccharide Receptors
0
Ptpns1 protein, mouse
0
Receptors, Immunologic
0
Toll-Like Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2361Références
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
pubmed: 24830344
pmcid: 4757912
Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).
pubmed: 12376594
Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).
pubmed: 12612579
Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351–358 (2007).
pubmed: 17322887
Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).
pubmed: 23471412
pmcid: 3622085
Perry, J. S. et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41, 414–426 (2014).
pubmed: 25220213
pmcid: 4175925
Leventhal, D. S. et al. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44, 847–859 (2016).
pubmed: 27037189
pmcid: 4842258
Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).
pubmed: 15492126
pmcid: 2211843
Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505–1513 (2009).
pubmed: 19564355
pmcid: 2715082
Perry, J. S. A. et al. Transfer of cell-surface antigens by scavenger receptor CD36 promotes thymic regulatory t cell receptor repertoire development and allo-tolerance. Immunity 48, 1271 (2018).
pubmed: 29924978
pmcid: 6015728
Lancaster, J. N. et al. Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance. Nat. Commun. 10, 2220 (2019).
pubmed: 31101805
pmcid: 6525199
Li, J., Park, J., Foss, D. & Goldschneider, I. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med. 206, 607–622 (2009).
pubmed: 19273629
pmcid: 2699131
Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).
pubmed: 25033907
pmcid: 4638219
Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438–450 (2012).
pubmed: 22444632
pmcid: 3315699
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092–1100 (2006).
pubmed: 16951687
Kroger, C. J., Spidale, N. A., Wang, B. & Tisch, R. Thymic dendritic cell subsets display distinct efficiencies and mechanisms of intercellular MHC transfer. J. Immunol. 198, 249–256 (2017).
pubmed: 27895179
Leventhal, D. S. et al. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44, 847–859 (2016).
pubmed: 27037189
pmcid: 4842258
Lei, Y. et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383–394 (2011).
pubmed: 21300913
pmcid: 3039864
Baba, T., Nakamoto, Y. & Mukaida, N. Crucial contribution of thymic Sirp alpha+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183, 3053–3063 (2009).
pubmed: 19675159
Hu, Z. et al. CCR7 modulates the generation of thymic regulatory T cells by altering the composition of the thymic dendritic cell compartment. Cell Rep. 21, 168–180 (2017).
pubmed: 28978470
pmcid: 5639943
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
pubmed: 20404851
Abramson, J. & Anderson, G. Thymic Epithelial Cells. Annu Rev. Immunol. 35, 85–118 (2017).
pubmed: 28226225
Haljasorg, U. et al. A highly conserved NF-kappaB-responsive enhancer is critical for thymic expression of Aire in mice. Eur. J. Immunol. 45, 3246–3256 (2015).
pubmed: 26364592
LaFlam, T. N. et al. Identification of a novel cis-regulatory element essential for immune tolerance. J. Exp. Med. 212, 1993–2002 (2015).
pubmed: 26527800
pmcid: 4647269
Bernasconi, P. et al. Increased toll-like receptor 4 expression in thymus of myasthenic patients with thymitis and thymic involution. Am. J. Pathol. 167, 129–139 (2005).
pubmed: 15972959
pmcid: 1603452
Cavalcante, P. et al. Toll-like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity? Ann. N. Y Acad. Sci. 1413, 11–24 (2018).
pubmed: 29363775
Huang, H. B. et al. TLR4 is constitutively expressed in chick thymic epithelial cells. Vet. Immunol. Immunopathol. 158, 182–188 (2014).
pubmed: 24507560
Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8, 487–496 (2007).
pubmed: 17417641
Gordon, J. et al. Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev. Biol. 7, 69 (2007).
pubmed: 17577402
pmcid: 1906761
Hou, B., Reizis, B. & DeFranco, A. L. Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29, 272–282 (2008).
pubmed: 18656388
pmcid: 2847796
Sansom, S. N. et al. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res. 24, 1918–1931 (2014).
pubmed: 25224068
pmcid: 4248310
Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev. Immunol. 32, 659–702 (2014).
pubmed: 24655300
Vigne, S. et al. IL-36R ligands are potent regulators of dendritic and T cells. Blood 118, 5813–5823 (2011).
pubmed: 21860022
Becher, B., Tugues, S. & Greter, M. GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45, 963–973 (2016).
pubmed: 27851925
Zlotoff, D. A. et al. CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115, 1897–1905 (2010).
pubmed: 19965655
pmcid: 2837318
Dyer, D. P. et al. Chemokine receptor redundancy and specificity are context dependent. Immunity 50, 378–389.e375 (2019).
pubmed: 30784579
pmcid: 6382461
Belperio, J. A. et al. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J. Clin. Invest. 110, 1703–1716 (2002).
pubmed: 12464676
pmcid: 151632
Fields, J. K., Günther, S. & Sundberg, E. J. Structural Basis of IL-1 Family Cytokine Signaling. Front Immunol. 10, 1412 (2019).
pubmed: 31281320
pmcid: 6596353
Eckhart, L., Lippens, S., Tschachler, E. & Declercq, W. Cell death by cornification. Biochim Biophys. Acta 1833, 3471–3480 (2013).
pubmed: 23792051
Miller, C. N. et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559, 627–631 (2018).
pubmed: 30022164
pmcid: 6062473
Bornstein, C. et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature 559, 622–626 (2018).
pubmed: 30022162
Wang, J. et al. Hassall’s corpuscles with cellular-senescence features maintain IFNα production through neutrophils and pDC activation in the thymus. Int Immunol. 31, 127–139 (2019).
pubmed: 30534943
Kolodziejczyk, A. A., Kim, J. K., Svensson, V., Marioni, J. C. & Teichmann, S. A. The technology and biology of single-cell RNA sequencing. Mol. Cell 58, 610–620 (2015).
pubmed: 26000846
Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320.e1322 (2018).
pubmed: 30392957
pmcid: 6239889
Ardouin, L. et al. Broad and largely concordant molecular changes characterize tolerogenic and immunogenic dendritic cell maturation in thymus and periphery. Immunity 45, 305–318 (2016).
pubmed: 27533013
Hettinger, J. et al. Origin of monocytes and macrophages in a committed progenitor. Nat. Immunol. 14, 821–830 (2013).
pubmed: 23812096
Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 11, 512–519 (2010).
pubmed: 20431619
McCaughtry, T. M., Wilken, M. S. & Hogquist, K. A. Thymic emigration revisited. J. Exp. Med. 204, 2513–2520 (2007).
pubmed: 17908937
pmcid: 2118501
Thiault, N. et al. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16, 628–634 (2015).
pubmed: 25939024
Owen, D. L. et al. Thymic regulatory T cells arise via two distinct developmental programs. Nat. Immunol. 20, 195–205 (2019).
pubmed: 30643267
pmcid: 6650268
Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).
pubmed: 12682220
Drobek, A. et al. Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells. EMBO J 37, e98518 (2018).
pubmed: 29752423
pmcid: 6043851
Gray, D. H., Gavanescu, I., Benoist, C. & Mathis, D. Danger-free autoimmune disease in Aire-deficient mice. Proc. Natl Acad. Sci. USA 104, 18193–18198 (2007).
pubmed: 17991771
Yano, M. et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 205, 2827–2838 (2008).
pubmed: 19015306
pmcid: 2585853
White, A. J. et al. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185, 4769–4776 (2010).
pubmed: 20861360
Lancaster, J. N., Li, Y. & Ehrlich, L. I. R. Chemokine-mediated choreography of thymocyte development and selection. Trends Immunol. 39, 86–98 (2018).
pubmed: 29162323
Klein, L. Dead man walking: how thymocytes scan the medulla. Nat. Immunol. 10, 809–811 (2009).
pubmed: 19621041
Yamano, T. et al. Thymic B cells are licensed to present self antigens for Central T cell tolerance induction. Immunity 42, 1048–1061 (2015).
pubmed: 26070482
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
pubmed: 19237601
pmcid: 2699126
Román, E., Shino, H., Qin, F. X. & Liu, Y. J. Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J. Immunol. 185, 3819–3823 (2010).
pubmed: 20802149
pmcid: 3325783
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
pubmed: 10795741
Coquet, J. M. et al. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med 210, 715–728 (2013).
pubmed: 23547099
pmcid: 3620350
Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl Acad. Sci. USA 105, 19869–19874 (2008).
pubmed: 19073916
Cowan, J. E. et al. Aire controls the recirculation of murine Foxp3. Eur. J. Immunol. 48, 844–854 (2018).
pubmed: 29285761
pmcid: 6001551
Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).
pubmed: 1547488
Janowska-Wieczorek, A. et al. Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment. Blood 98, 3143–3149 (2001).
pubmed: 11698303
Liu, L. et al. Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2. Genesis 51, 587–595 (2013).
pubmed: 23650205
pmcid: 3753089
Hashimoto, K., Joshi, S. K. & Koni, P. A. A conditional null allele of the major histocompatibility IA-beta chain gene. Genesis 32, 152–153 (2002).
pubmed: 11857806
Caton, M. L., Smith-Raska, M. R. & Reizis, B. Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J. Exp. Med 204, 1653–1664 (2007).
pubmed: 17591855
pmcid: 2118632
Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).
pubmed: 20023653
de Boer, J. et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314–325 (2003).
pubmed: 12548562
Sommers, C. L. et al. Function of CD3 epsilon-mediated signals in T cell development. J. Exp. Med. 192, 913–919 (2000).
pubmed: 10993922
pmcid: 2193290
Kurts, C., Miller, J. F., Subramaniam, R. M., Carbone, F. R. & Heath, W. R. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J. Exp. Med. 188, 409–414 (1998).
pubmed: 9670054
pmcid: 2212442
Palmer, E., Drobek, A. & Stepanek, O. Opposing effects of actin signaling and LFA-1 on establishing the affinity threshold for inducing effector T cell responses in mice. Eur. J. Immunol. 46, 1887–1901 (2016).
pubmed: 27188212
Barnden, M. J., Allison, J., Heath, W. R. & Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).
pubmed: 9553774
Dobeš, J. et al. A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire. Eur. J. Immunol. 48, 546–548 (2018).
pubmed: 29193031
Liu, L. L. et al. A simplified intrathymic injection technique for mice. Biotech. Histochem. 87, 140–147 (2012).
pubmed: 21539502
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
pubmed: 11328886
pmcid: 55695
Smith, T., Heger, A. & Sudbery, I. UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy. Genome Res. 27, 491–499 (2017).
pubmed: 28100584
pmcid: 5340976
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
pubmed: 29608179
pmcid: 29608179