Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells

Journal of Neuroinflammation

Dale S Gregerson¹  Mark J Pierson¹  Neal D Heuss¹  Scott W McPherson¹ 

[1] Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Rm. 310, Lion’s Research Bldg.,2001 6th St. SE., Minneapolis 55455-3007, Minnesota, USA

关键词: dendritic cells;    autoimmunity;    peripheral regulatory T cells;    regulatory T cells;   

Others  :  1149925
DOI  :  10.1186/s12974-014-0205-4

 received in 2014-10-14, accepted in 2014-11-20,  发布年份 2014

【 摘 要 】

Background

We previously reported that the peripheral regulatory T cells (pTregs) generated ‘on-demand’ in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Here, we expanded these findings by examining whether locally generated, locally acting pTregs were protective against spontaneous autoimmunity and autoimmunity mediated by interphotoreceptor retinoid-binding protein (IRBP). We also examined the APC capacity of retinal DC in vivo.

Methods

Transgenic (Tg) mice expressing diphtheria toxin receptor (DTR) and/or green fluorescent protein (GFP) under control of the endogenous FoxP3 promoter (GFP only in FG mice, GFP and DTR in FDG mice) or the CD11c promoter (GFP and DTR in CDG mice) were used in conjunction with Tg mice expressing beta-galactosidase (βgal) as retinal neo-self antigen and βgal-specific TCR Tg mice (BG2). Retinal T cell responses were assayed by flow cytometry and retinal autoimmune disease assessed by histological examination.

Results

Local depletion of the Tregs enhanced actively induced experimental autoimmune uveoretinitis to the highly expressed retinal self-antigen IRBP in FDG mice and spontaneous autoimmunity in βgal-FDG-BG2 mice, but not in mice lacking autoreactive T cells or their target antigen in the retina. The presence of retinal βgal downregulated the generation of antigen-specific Teffs and pTregs within the retina in response to local βgal challenge. Retinal DC depletion prevented generation of Tregs and Teffs within retina after βgal injection. Microglia remaining after DC depletion did not make up for loss of DC-dependent antigen presentation.

Conclusions

Our results suggest that local retinal Tregs protect against spontaneous organ-specific autoimmunity and that T cell responses within the retina require the presence of local DC.

【 授权许可】

   
2014 McPherson et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 3.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Jutel M, Akdis CA: T-cell regulatory mechanisms in specific immunotherapy. Chem Immunol Allergy 2008, 94:158-177.
• [2]Shevach EM: From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006, 25:195-201.
• [3]Hill JA, Benoist C, Mathis D: Treg cells: guardians for life. Nat Immunol 2007, 8:124-125.
• [4]Kim JM, Rasmussen JP, Rudensky AY: Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007, 8:191-197.
• [5]Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF: Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 2013, 14:307-308.
• [6]Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, Wise PM, Chen A, Zheng YQ, Simpson PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA, Williams CB: A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 2011, 35:109-122.
• [7]Erlebacher A: Mechanisms of T cell tolerance towards the allogeneic fetus. Nat Rev Immunol 2013, 13:23-33.
• [8]Rowe JH, Ertelt JM, Xin L, Way SS: Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 2012, 490:102-106.
• [9]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, 150:29-38.
• [10]de Lafaille MAC, Lafaille JJ: Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009, 30:626-635.
• [11]Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY: Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 2012, 482:395-399.
• [12]de Lafaille MAC, Kutchukhidze N, Shen S, Ding Y, Yee H, Lafaille JJ: Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 2008, 29:114-126.
• [13]Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM: Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010, 184:3433-3441.
• [14]Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P, Weiss D, Von Schack D, Bluestone JA: Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 2012, 209:1713-1722. S1711-1719
• [15]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:e24226.
• [16]Gottschalk RA, Corse E, Allison JP: Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol 2012, 188:976-980.
• [17]Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK: Helios + and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol 2013, 190:2001-2008.
• [18]Yadav M, Stephan S, Bluestone JA: Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front Immunol 2013, 4:232.
• [19]Weiss JM, Bilate AM, Gobert M, Ding Y, de Lafaille MA C, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG, Yang Y, Floess S, Huehn J, Oh S, Li MO, Niec RE, Rudensky AY, Dustin ML, Littman DR, Lafaille JJ: Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 2012, 209:1723-1742. S1721
• [20]DiPaolo RJ, Brinster C, Davidson TS, Andersson J, Glass D, Shevach EM: Autoantigen-specific TGFbeta-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells. J Immunol 2007, 179:4685-4693.
• [21]Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, Mikulski Z, Khorram N, Rosenthal P, Broide DH, Croft M: Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med 2013, 210:775-788.
• [22]Xu H, Chen M, Reid DM, Forrester JV: LYVE-1-positive macrophages are present in normal murine eyes. Invest Ophthalmol Vis Sci 2007, 48:2162-2171.
• [23]Niederkorn JY: See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 2006, 7:354-359.
• [24]Keino H, Watanabe T, Sato Y, Okada AA: Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis. Br J Ophthalmol 2010, 94:802-807.
• [25]Zhou R, Horai R, Silver PB, Mattapallil MJ, Zarate-Blades CR, Chong WP, Chen J, Rigden RC, Villasmil R, Caspi RR: The living eye “disarms” uncommitted autoreactive T cells by converting them to Foxp3(+) regulatory cells following local antigen recognition. J Immunol 2012, 188:1742-1750.
• [26]McPherson SW, Heuss ND, Gregerson DS: Local “on-demand” generation and function of antigen-specific Foxp3+ regulatory T cells. J Immunol 2013, 190:4971-4981.
• [27]Gallegos AM, Bevan MJ: Central tolerance: good but imperfect. Immunol Rev 2006, 209:290-296.
• [28]Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, Cron RQ, Shacka JJ, Raman C, Standaert DG: MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 2013, 33:9592-9600.
• [29]Jaini R, Popescu DC, Flask CA, Macklin WB, Tuohy VK: Myelin antigen load influences antigen presentation and severity of central nervous system autoimmunity. J Neuroimmunol 2013, 259:37-46.
• [30]Jarry U, Jeannin P, Pineau L, Donnou S, Delneste Y, Couez D: Efficiently stimulated adult microglia cross-prime naive CD8+ T cells injected in the brain. Eur J Immunol 2013, 43:1173-1184.
• [31]Scheffel J, Regen T, Van Rossum D, Seifert S, Ribes S, Nau R, Parsa R, Harris RA, Boddeke HW, Chuang HN, Pukrop T, Wessels JT, Jurgens T, Merkler D, Bruck W, Schnaars M, Simons M, Kettenmann H, Hanisch UK: Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia. Glia 2012, 60:1930-1943.
• [32]Almolda B, Gonzalez B, Castellano B: Antigen presentation in EAE: role of microglia, macrophages and dendritic cells. Front Biosci (Landmark Ed) 2011, 16:1157-1171.
• [33]Steinbach K, Piedavent M, Bauer S, Neumann JT, Friese MA: Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. J Immunol 2013, 191:4531-4539.
• [34]Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B: Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 2005, 11:328-334.
• [35]McMahon EJ, Bailey SL, Miller SD: CNS dendritic cells: critical participants in CNS inflammation? Neurochem Int 2006, 49:195-203.
• [36]Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD: Turnover of resident retinal microglia in the normal adult mouse. Glia 2007, 55:1189-1198.
• [37]Xu H, Dawson R, Forrester JV, Liversidge J: Identification of novel dendritic cell populations in normal mouse retina. Invest Ophthalmol Vis Sci 2007, 48:1701-1710.
• [38]D’Agostino PM, Gottfried-Blackmore A, Anandasabapathy N, Bulloch K: Brain dendritic cells: biology and pathology. Acta Neuropathol 2012, 124:599-614.
• [39]Heuss ND, Lehmann U, Norbury CC, McPherson SW, Gregerson DS: Local activation of dendritic cells alters the pathogenesis of autoimmune disease in the retina. J Immunol 2012, 188:1191-1200.
• [40]Lehmann U, Heuss ND, McPherson SW, Roehrich H, Gregerson DS: Dendritic cells are early responders to retinal injury. Neurobiol Dis 2010, 40:177-184.
• [41]Kikuchi T, Raju K, Breitman ML, Shinohara T: The proximal promoter of the mouse arrestin gene directs gene expression in photoreceptor cells and contains an evolutionarily conserved retinal factor-binding site. Mol Cell Biol 1993, 13:4400-4408.
• [42]Kimura A, Singh D, Wawrousek EF, Kikuchi M, Nakamura M, Shinohara T: Both PCE-1/RX and OTX/CRX interactions are necessary for photoreceptor- specific gene expression. J Biol Chem 2000, 275:1152-1160.
• [43]Gregerson DS, Torseth JW, McPherson SW, Roberts JP, Shinohara T, Zack DJ: Retinal expression of a neo-self antigen, beta-galactosidase, is not tolerogenic and creates a target for autoimmune uveoretinitis. J Immunol 1999, 163:1073-1080.
• [44]McPherson SW, Heuss ND, Gregerson DS: Lymphopenia-induced proliferation is a potent activator for CD4+ T cell-mediated autoimmune disease in the retina. J Immunol 2009, 182:969-979.
• [45]Tewalt EF, Grant JM, Granger EL, Palmer DC, Heuss ND, Gregerson DS, Restifo NP, Norbury CC: Viral sequestration of antigen subverts cross presentation to CD8(+) T cells. PLoS Pathog 2009, 5:e1000457.
• [46]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, 22:329-341.
• [47]Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, Pamer EG, Littman DR, Lang RA: In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 2002, 17:211-220.
• [48]Mattapallil MJ, Wawrousek EF, Chan CC, Zhao H, Roychoudhury J, Ferguson TA, Caspi RR: The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6 N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci 2012, 53:2921-2927.
• [49]Gregerson DS, Dou C: Spontaneous induction of immunoregulation by an endogenous retinal protein. Invest Ophthalmol Vis Sci 2002, 43:2984-2991.
• [50]Gregerson DS, Heuss ND, Lehmann U, McPherson SW: Peripheral induction of tolerance by retinal antigen expression. J Immunol 2009, 183:814-822.
• [51]Gregerson DS, Obritsch WF, Donoso LA: Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols. J Immunol 1993, 151:5751-5761.
• [52]Thorstenson KM, Khoruts A: Generation of anergic and potentially immunoregulatory CD25 + CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 2001, 167:188-195.
• [53]Marie JC, Letterio JJ, Gavin M, Rudensky AY: TGF-beta1 maintains suppressor function and Foxp3 expression in CD4 + CD25+ regulatory T cells. J Exp Med 2005, 201:1061-1067.
• [54]Setoguchi R, Hori S, Takahashi T, Sakaguchi S: Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005, 201:723-735.
• [55]Simonetta F, Gestermann N, Martinet KZ, Boniotto M, Tissieres P, Seddon B, Bourgeois C: Interleukin-7 influences FOXP3 + CD4+ regulatory T cells peripheral homeostasis. PLoS One 2012, 7:e36596.
• [56]Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA: Cutting edge: CD28 controls peripheral homeostasis of CD4 + CD25+ regulatory T cells. J Immunol 2003, 171:3348-3352.
• [57]Egwuagu CE, Charukamnoetkanok P, Gery I: Thymic expression of autoantigens correlates with resistance to autoimmune disease. J Immunol 1997, 159:3109-3112.
• [58]Agarwal RK, Silver PB, Caspi RR: Rodent models of experimental autoimmune uveitis. Methods Mol Biol 2012, 900:443-469.
• [59]Heuss ND, Pierson MJ, Montaniel K, McPherson SW, Lehmann U, Hussong SA, Ferrington DA, Low WC, Gregerson DS: Retinal dendritic cell recruitment, but not function, was inhibited in MyD88 and TRIF deficient mice. J Neuroinflammation 2014, 11:143. BioMed Central Full Text
• [60]McPherson SW, Heuss ND, Gregerson DS: Regulation of CD8(+) T cell responses to retinal antigen by local FoxP3(+) regulatory T cells. Front Immunol 2012, 3:166.
• [61]Hogquist KA, Tomlinson AJ, Kieper WC, McGargill MA, Hart MC, Naylor S, Jameson SC: Identification of a naturally occurring ligand for thymic positive selection. Immunity 1997, 6:389-399.
• [62]Morris GP, Allen PM: How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 2012, 13:121-128.
• [63]Avichezer D, Grajewski RS, Chan CC, Mattapallil MJ, Silver PB, Raber JA, Liou GI, Wiggert B, Lewis GM, Donoso LA, Caspi RR: An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms. J Exp Med 2003, 198:1665-1676.
• [64]DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi R, Fong L, Anderson MS: Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med 2006, 203:2727-2735.
• [65]Bridges CD, Price J, Landers RA, Fong SL, Liou GI, Hong BS, Tsin AT: Interstitial retinol-binding protein (IRBP) in subretinal fluid. Invest Ophthalmol Vis Sci 1986, 27:1027-1030.
• [66]Jeon CJ, Strettoi E, Masland RH: The major cell populations of the mouse retina. J Neurosci 1998, 18:8936-8946.
• [67]Panda-Jonas S, Jonas JB, Jakobczyk M, Schneider U: Retinal photoreceptor count, retinal surface area, and optic disc size in normal human eyes. Ophthalmology 1994, 101:519-523.
• [68]Taylor E, Jennings A: Calculation of total retinal area. Br J Ophthalmol 1971, 55:262-265.
• [69]Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007, 204:1757-1764.
• [70]Daniel C, von Boehmer H: Extrathymic generation of regulatory T cells–chances and challenges for prevention of autoimmune disease. Adv Immunol 2011, 112:177-213.
• [71]Mucida D, Pino-Lagos K, Kim G, Nowak E, Benson MJ, Kronenberg M, Noelle RJ, Cheroutre H: Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity 2009, 30:471-472. author reply 472–473
• [72]Zhou R, Horai R, Mattapallil MJ, Caspi RR: A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid. J Immunol 2011, 187:4170-4177.
• [73]Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A, Jenkins MK, Anderson MS: Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc Natl Acad Sci U S A 2012, 109:7847-7852.
• [74]Cortes LM, Mattapallil MJ, Silver PB, Donoso LA, Liou GI, Zhu W, Chan CC, Caspi RR: Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 2008, 49:1946-1956.
• [75]Goverman J, Brabb T, Paez A, Harrington C, von Dassow P: Initiation and regulation of CNS autoimmunity. Crit Rev Immunol 1997, 17:469-480.
• [76]Horai R, Silver PB, Chen J, Agarwal RK, Chong WP, Jittayasothorn Y, Mattapallil MJ, Nguyen S, Natarajan K, Villasmil R, Wang P, Karabekian Z, Lytton SD, Chan CC, Caspi RR: Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. J Autoimmun 2013, 44:21-33.
• [77]Lambe T, Leung JC, Ferry H, Bouriez-Jones T, Makinen K, Crockford TL, Jiang HR, Nickerson JM, Peltonen L, Forrester JV, Cornall RJ: Limited peripheral T cell anergy predisposes to retinal autoimmunity. J Immunol 2007, 178:4276-4283.
• [78]Zarate-Blades CR, Horai R, Chen J, Silver PB, Dillenburg-Pilla P, Yamane H, Chan CC, Honda K, Caspi R: Activation of autoreactive T cells by endogenous microflora induces spontaneous autoimmunity in the immunologically privileged retina (BA8P.130). J Immunol 2014, 192:113-113.
• [79]Caspi RR: Understanding autoimmunity in the eye: from animal models to novel therapies. Discov Med 2014, 17:155-162.
• [80]Wildner G, Diedrichs-Mohring M: Autoimmune uveitis and antigenic mimicry of environmental antigens. Autoimmun Rev 2004, 3:383-387.
• [81]Chen J, Qian H, Horai R, Chan CC, Falick Y, Caspi RR: Comparative analysis of induced vs. spontaneous models of autoimmune uveitis targeting the interphotoreceptor retinoid binding protein. PLoS One 2013, 8:e72161.
• [82]Pauken KE, Linehan JL, Spanier JA, Sahli NL, Kalekar LA, Binstadt BA, Moon JJ, Mueller DL, Jenkins MK, Fife BT: Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice. J Immunol 2013, 191:4913-4917.
• [83]Wells AD: New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 2009, 182:7331-7341.
• [84]Shi G, Lovaas JD, Tan C, Vistica BP, Wawrousek EF, Aziz MK, Rigden RC, Caspi RR, Gery I: Cell-cell interaction with APC, not IL-23, is required for naive CD4 cells to acquire pathogenicity during Th17 lineage commitment. J Immunol 2012, 189:1220-1227.
• [85]Forrester JV, Liversidge J, Dua HS: Regulation of the local immune response by retinal cells. Curr Eye Res 1990, 9:183-191.
• [86]Wang Y, Calder VL, Lightman SL, Greenwood J: Antigen presentation by rat brain and retinal endothelial cells. J Neuroimmunol 1995, 61:231-239.
• [87]Detrick B, Hooks JJ: Immune regulation in the retina. Immunol Res 2010, 47:153-161.
• [88]Gregerson DS, Heuss ND, Lew KL, McPherson SW, Ferrington DA: Interaction of retinal pigmented epithelial cells and CD4 T cells leads to T-cell anergy. Invest Ophthalmol Vis Sci 2007, 48:4654-4663.