Thymically-derived Foxp3+ regulatory T cells are the primary regulators of type 1 diabetes in the non-obese diabetic mouse model
Autoři:
Daniel R. Holohan aff001; Frédéric Van Gool aff001; Jeffrey A. Bluestone aff001
Působiště autorů:
Diabetes Center, University of California, San Francisco, San Francisco, CA, United States of America
aff001; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States of America
aff002
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0217728
Souhrn
Regulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1-/- mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1-/- mice. Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.
Klíčová slova:
Cell staining – Microbiome – Mouse models – Regulatory T cells – T cells – Thymus – Insulitis
Zdroje
1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic Self-Tolerance Maintained by activated T cells expressing IL-2 Receptor a-chains (CD25): Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases. J Immunol. 1996;155:1151–64.
2. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic Self-Tolerance Maintained by Cd25 + Cd4 + Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4. J Exp Med. 2000;17(192):303–10.
3. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3.[see comment]. Science. 2003;299(5609):1057–61. doi: 10.1126/science.1079490 12522256
4. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6. doi: 10.1038/ni904 12612578
5. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity. 2005;22(3):329–41. doi: 10.1016/j.immuni.2005.01.016 15780990
6. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12(4):431–40. doi: 10.1016/s1074-7613(00)80195-8 10795741
7. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. doi: 10.1038/83707 11137992
8. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+T regulatory cells. Nat Immunol. 2003;4(4):337–42. doi: 10.1038/ni909 12612581
9. Brode S, Raine T, Zaccone P, Cooke A. Cyclophosphamide-Induced Type-1 Diabetes in the NOD Mouse Is Associated with a Reduction of CD4+CD25+Foxp3+ Regulatory T Cells. J Immunol. 2006;177(10):6603–12. doi: 10.4049/jimmunol.177.10.6603 17082572
10. Feuerer M, Shen Y, Littman DR, Benoist C, Mathis D. How Punctual Ablation of Regulatory T Cells Unleashes an Autoimmune Lesion within the Pancreatic Islets. Immunity. 2009;31(4):654–64. doi: 10.1016/j.immuni.2009.08.023 19818653
11. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–6. doi: 10.1038/86302 11276200
12. Apostolou I, Sarukhan A, Klein L, Von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002;3(8):2–9.
13. Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N, et al. Conversion of Peripheral CD4 + CD25 − Naive T Cells to CD4 + CD25 + Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3. J Exp Med. 2003;198(12):1875–86. doi: 10.1084/jem.20030152 14676299
14. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204(8):1765–74. doi: 10.1084/jem.20070719 17620363
15. Coombes JL, Siddiqui KRR, Arancibia-Cárcamo C V., Hall J, Sun C-M, Belkaid Y, et al. A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-β–and retinoic acid–dependent mechanism. J Exp Med. 2007;204(8):1757–64. doi: 10.1084/jem.20070590 17620361
16. Sun C-M, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204(8):1775–85. doi: 10.1084/jem.20070602 17620362
17. Apostolou I, von Boehmer H. In Vivo Instruction of Suppressor Commitment in Naive T Cells. J Exp Med. 2004;199(10):1401–8. doi: 10.1084/jem.20040249 15148338
18. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto De Lafaille MA. Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest. 2005;115(7):1923–33. doi: 10.1172/JCI24487 15937545
19. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6(12):1219–27. doi: 10.1038/ni1265 16244650
20. Feuerer M, Jiang W, Holler PD, Satpathy A, Campbell C, Bogue M, et al. Enhanced thymic selection of FoxP3 ؉ regulatory T cells in the NOD mouse model of autoimmune diabetes. 2007;104(46):18181–6.
21. Ferreira C, Palmer D, Blake K, Garden OA, Dyson J. Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus. J Immunol. 2014;192(9):4145–52. doi: 10.4049/jimmunol.1301600 24663675
22. Kern J, Drutel R, Leanhart S, Bogacz M, Pacholczyk R. Reduction of T cell receptor diversity in NOD mice prevents development of type 1 diabetes but not Sjögren’s syndrome. PLoS One. 2014;9(11).
23. Spence A, Purtha W, Tam J, Dong S, Kim Y, Ju C, et al. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. Proc Natl Acad Sci. 2018;115(24):5265–70.
24. Vergani A, D’Addio F, Jurewicz M, Petrelli A, Watanabe T, Liu K, et al. A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice. Diabetes. 2010;59(9):2253–64. doi: 10.2337/db09-1264 20805386
25. Ben Nasr M, Tezza S, D’Addio F, Mameli C, Usuelli V, Maestroni A, et al. PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. Sci Transl Med. 2017;9(416):1–15.
26. Delong T, Baker RL, He J, Barbour G, Bradley B, Haskins K. Diabetogenic T-cell clones recognize an altered peptide of chromogranin A. Diabetes. 2012;61(12):3239–46. doi: 10.2337/db12-0112 22912420
27. Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351(6274):711–4. doi: 10.1126/science.aad2791 26912858
28. Baker RL, Jamison BL, Wiles TA, Lindsay RS, Barbour G, Bradley B, et al. CD4 T cells reactive to hybrid insulin peptides are indicators of disease activity in the NOD mouse. Diabetes. 2018;67(9):1836–46. doi: 10.2337/db18-0200 29976617
29. Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP, et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med. 2005;202(9):1191–7. doi: 10.1084/jem.20051251 16260488
30. Van Lummel M, Duinkerken G, Van Veelen PA, De Ru A, Cordfunke R, Zaldumbide A, et al. Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes. 2014;63(1):237–47. doi: 10.2337/db12-1214 24089515
31. McGinty JW, Chow IT, Greenbaum C, Odegard J, Kwok WW, James EA. Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes. 2014;63(9):3033–40. doi: 10.2337/db13-1952 24705406
32. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35(1):109–22. doi: 10.1016/j.immuni.2011.03.029 21723159
33. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012;209(10):1713–22. doi: 10.1084/jem.20120822 22966003
34. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3 + T reg cells. J Exp Med. 2012;209(10):1723–42. doi: 10.1084/jem.20120914 22966001
35. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3 + T Regulatory Cells. J Immunol. 2010;184(7):3433–41. doi: 10.4049/jimmunol.0904028 20181882
36. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS One. 2011;6(8).
37. Gottschalk RA, Corse E, Allison JP. Expression of Helios in Peripherally Induced Foxp3+ Regulatory T Cells. J Immunol. 2012;189(2):500–500. doi: 10.4049/jimmunol.1290033
38. Szurek E, Cebula A, Wojciech L, Pietrzak M, Rempala G, Kisielow P, et al. Differences in expression level of Helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4+Foxp3+ regulatory T cells. PLoS One. 2015;10(10):1–16.
39. Nutsch K, Chai JN, Ai TL, Russler-Germain E, Feehley T, Nagler CR, et al. Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery. Cell Rep. 2016;17(1):206–20. doi: 10.1016/j.celrep.2016.08.092 27681432
40. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010;463(7282):808–12. doi: 10.1038/nature08750 20072126
41. Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, et al. Loss of integrin a v b 8 on dendritic cells causes autoimmunity and colitis in mice. 2007;449(September):361–6.
42. Schallenberg S, Tsai P-Y, Riewaldt J, Kretschmer K. Identification of an immediate Foxp3 − precursor to Foxp3 + regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J Exp Med. 2010;207(7):1393. doi: 10.1084/jem.20100045 20584884
43. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, et al. Extrathymically generated regulatory T cells control mucosal T H 2 inflammation. Nature. 2012;482(7385):395–9. doi: 10.1038/nature10772 22318520
44. Arpaia N, Campbell C, Fan X, Dikiy S, Van Der Veeken J, Deroos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451–5. doi: 10.1038/nature12726 24226773
45. Campbell C, Dikiy S, Bhattarai SK, Chinen T, Matheis F, Calafiore M, et al. Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance. Immunity. 2018;1–13.
46. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell. 2012;150(1):29–38. doi: 10.1016/j.cell.2012.05.031 22770213
47. Schlenner SM, Weigmann B, Ruan Q, Chen Y, von Boehmer H. Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J Exp Med. 2012;209(9):1529–35. doi: 10.1084/jem.20112646 22908322
48. Petzold C, Steinbronn N, Gereke M, Strasser RH, Sparwasser T, Bruder D, et al. Fluorochrome-based definition of naturally occurring Foxp3+regulatory T cells of intra- and extrathymic origin. Eur J Immunol. 2014;44(12):3632–45. doi: 10.1002/eji.201444750 25159127
49. Schuster C, Jonas F, Zhao F, Kissler S. Peripherally-induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model. Eur J Immunol. 2018;1–6. doi: 10.1002/eji.201871000
50. Ohnmacht C, Park J-H, Cording S, Wing JB, Atarashi K, Obata Y, et al. The microbiota regulates type 2 immunity through RORyt+ T cells. Science. 2015;349(6251):989–93. doi: 10.1126/science.aac4263 26160380
51. Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, et al. Individual intestinal symbionts induce a distinct population of RORyt+ regulatory T cells. Science. 2015;349(6251):993–7. doi: 10.1126/science.aaa9420 26272906
52. Yang BH, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, et al. Foxp3+T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 2016;9(2):444–57. doi: 10.1038/mi.2015.74 26307665
53. Solomon BD, Hsieh C-S. Antigen-Specific Development of Mucosal Foxp3 + RORγt + T Cells from Regulatory T Cell Precursors. J Immunol. 2016;197(9):3512–9. doi: 10.4049/jimmunol.1601217 27671109
54. Crawford F, Stadinski B, Jin N, Michels A, Nakayama M, Pratt P, et al. Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci. 2011;108(40):16729–34. doi: 10.1073/pnas.1113954108 21949373
55. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein. Science. 2002;298(5997):1395–401.
56. Pozzilli P, Signore A, Williams AJK, Beales PE. NOD mouse colonies around the world- recent facts and figures. Immunol Today. 1993;14(5):193–6. doi: 10.1016/0167-5699(93)90160-M 8517916
57. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455(7216):1109–13. doi: 10.1038/nature07336 18806780
58. Markle JGM, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8. doi: 10.1126/science.1233521 23328391
59. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–12. doi: 10.1016/j.immuni.2013.08.013 23973225
60. Hu Y, Peng J, Li F, Wong FS, Wen L. Evaluation of different mucosal microbiota leads to gut microbiota-based prediction of type 1 diabetes in NOD mice. Sci Rep. 2018;8(1):1–13. doi: 10.1038/s41598-017-17765-5
61. Turley SJ, Lee J-W, Dutton-Swain N, Mathis D, Benoist C. Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc Natl Acad Sci. 2005;102(49):17729–33. doi: 10.1073/pnas.0509006102 16317068
62. Tai N, Peng J, Liu F, Gulden E, Hu Y, Zhang X, et al. Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice. J Exp Med. 2016;213(10):2129–46. doi: 10.1084/jem.20160526 27621416
63. Culina S, Lalanne AI, Afonso G, Cerosaletti K, Pinto S, Sebastiani G, et al. Islet-reactive CD8 + T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol. 2018;3(20):eaao4013.
64. Szot GL, Koudria P, Bluestone JA. Murine Pancreatic Islet Isolation. 2007;1640:7–8.
65. Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017;7(1):1–7. doi: 10.1038/s41598-016-0028-x
Článek vyšel v časopise
PLOS One
2019 Číslo 10
- Proč se v Česku šíří několik „vymýcených“ infekcí najednou? Ptáme se odborníků
- ADHD jako evoluční výhoda? Výzkum se zaměřil na lovce a sběrače
- Není migréna jako migréna: Co pociťují ženy a co muži?
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Není statin jako statin aneb praktický přehled rozdílů jednotlivých molekul
Nejčtenější v tomto čísle
- Correction: Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study
- Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity
- Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs)
- Risk factors associated with IgA vasculitis with nephritis (Henoch–Schönlein purpura nephritis) progressing to unfavorable outcomes: A meta-analysis
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy