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http://dx.doi.org/10.5051/jpis.2017.47.5.292

Targeting the epitope spreader Pep19 by naïve human CD45RA+ regulatory T cells dictates a distinct suppressive T cell fate in a novel form of immunotherapy  

Kim, Hyun-Joo (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Cha, Gil Sun (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Joo, Ji-Young (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Lee, Juyoun (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Kim, Sung-Jo (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Lee, Jeongae (Molecular Recognition Research Center, Korea Institute of Science and Technology)
Park, So Youn (Department of Pharmacology, Pusan National University School of Medicine)
Choi, Jeomil (Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry)
Publication Information
Journal of Periodontal and Implant Science / v.47, no.5, 2017 , pp. 292-311 More about this Journal
Abstract
Purpose: Beyond the limited scope of non-specific polyclonal regulatory T cell (Treg)-based immunotherapy, which depends largely on serendipity, the present study explored a target Treg subset appropriate for the delivery of a novel epitope spreader Pep19 antigen as part of a sophisticated form of immunotherapy with defined antigen specificity that induces immune tolerance. Methods: Human polyclonal $CD4^+CD25^+CD127^{lo-}$ Tregs (127-Tregs) and $na\ddot{i}ve$ $CD4^+CD25^+CD45RA^+$ Tregs (45RA-Tregs) were isolated and were stimulated with target peptide 19 (Pep19)-pulsed dendritic cells in a tolerogenic milieu followed by ex vivo expansion. Low-dose interleukin-2 (IL-2) and rapamycin were added to selectively exclude the outgrowth of contaminating effector T cells (Teffs). The following parameters were investigated in the expanded antigen-specific Tregs: the distinct expression of the immunosuppressive Treg marker Foxp3, epigenetic stability (demethylation in the Treg-specific demethylated region), the suppression of Teffs, expression of the homing receptors CD62L/CCR7, and CD95L-mediated apoptosis. The expanded Tregs were adoptively transferred into an $NOD/scid/IL-2R{\gamma}^{-/-}$ mouse model of collagen-induced arthritis. Results: Epitope-spreader Pep19 targeting by 45RA-Tregs led to an outstanding in vitro suppressive T cell fate characterized by robust ex vivo expansion, the salient expression of Foxp3, high epigenetic stability, enhanced T cell suppression, modest expression of CD62L/CCR7, and higher resistance to CD95L-mediated apoptosis. After adoptive transfer, the distinct fate of these T cells demonstrated a potent in vivo immunotherapeutic capability, as indicated by the complete elimination of footpad swelling, prolonged survival, minimal histopathological changes, and preferential localization of $CD4^+CD25^+$ Tregs at the articular joints in a mechanistic and orchestrated way. Conclusions: We propose human $na\ddot{i}ve$ $CD4^+CD25^+CD45RA^+$ Tregs and the epitope spreader Pep19 as cellular and molecular targets for a novel antigen-specific Treg-based vaccination against collagen-induced arthritis.
Keywords
Adoptive transfer; Autoimmune diseases; Heat-shock proteins; Immune tolerance; Regulatory T-lymphocytes; Rheumatoid arthritis;
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1 Ait-Oufella H, Salomon BL, Potteaux S, Robertson AK, Gourdy P, Zoll J, et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006;12:178-80.   DOI
2 Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 2015;7:315ra189.   DOI
3 Miyara M, Ito Y, Sakaguchi S. Treg-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol 2014;10:543-51.   DOI
4 Bluestone JA, Bour-Jordan H. Current and future immunomodulation strategies to restore tolerance in autoimmune diseases. Cold Spring Harb Perspect Biol 2012;4:a007542.
5 Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the Foxp3 transcription factor. Immunity 2009;30:899-911.   DOI
6 Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006;108:4260-7.   DOI
7 Hoffmann P, Boeld TJ, Eder R, Huehn J, Floess S, Wieczorek G, et al. Loss of Foxp3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol 2009;39:1088-97.   DOI
8 Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 2006;108:3371-8.   DOI
9 McMurchy AN, Bushell A, Levings MK, Wood KJ. Moving to tolerance: clinical application of T regulatory cells. Semin Immunol 2011;23:304-13.   DOI
10 Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004;199:1455-65.   DOI
11 Bluestone JA, Trotta E, Xu D. The therapeutic potential of regulatory T cells for the treatment of autoimmune disease. Expert Opin Ther Targets 2015;19:1091-103.   DOI
12 Fischbach MA, Bluestone JA, Lim WA. Cell-based therapeutics: the next pillar of medicine. Sci Transl Med 2013;5:179ps7.
13 Persson GR. Rheumatoid arthritis and periodontitis - inflammatory and infectious connections. Review of the literature. J Oral Microbiol 2012;4:11829.   DOI
14 Arleevskaya MI, Kravtsova OA, Lemerle J, Renaudineau Y, Tsibulkin AP. How Rheumatoid arthritis can result from provocation of the immune system by microorganisms and viruses. Front Microbiol 2016;7:1296.
15 Choi JI, Chung SW, Kang HS, Rhim BY, Park YM, Kim US, et al. Epitope mapping of Porphyromonas gingivalis heat-shock protein and human heat-shock protein in human atherosclerosis. J Dent Res 2004;83:936-40.   DOI
16 Choi J, Lee SY, Kim K, Choi BK. Identification of immunoreactive epitopes of the Porphyromonas gingivalis heat shock protein in periodontitis and atherosclerosis. J Periodontal Res 2011;46:240-5.   DOI
17 Jeong E, Lee JY, Kim SJ, Choi J. Predominant immunoreactivity of Porphyromonas gingivalis heat shock protein in autoimmune diseases. J Periodontal Res 2012;47:811-6.   DOI
18 Jeong E, Kim K, Kim JH, Cha GS, Kim SJ, Kang HS, et al. Porphyromonas gingivalis HSP60 peptides have distinct roles in the development of atherosclerosis. Mol Immunol 2015;63:489-96.   DOI
19 Kwon EY, Cha GS, Jeong E, Lee JY, Kim SJ, Surh CD, et al. Pep19 drives epitope spreading in periodontitis and periodontitis-associated autoimmune diseases. J Periodontal Res 2016;51:381-94.   DOI
20 Joo JY, Cha GS, Chung J, Lee JY, Kim SJ, Choi J. Peptide 19 of Porphyromonas gingivalis heat shock protein is a potent inducer of low-density lipoprotein oxidation. J Periodontol 2017;88:e58-64.   DOI
21 Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008;118:3537-45.   DOI
22 Haque M, Fino K, Lei F, Xiong X, Song J. Utilizing regulatory T cells against rheumatoid arthritis. Front Oncol 2014;4:209.
23 Zonneveld-Huijssoon E, Roord ST, de Jager W, Klein M, Albani S, Anderton SM, et al. Bystander suppression of experimental arthritis by nasal administration of a heat shock protein peptide. Ann Rheum Dis 2011;70:2199-206.   DOI
24 Overacre AE, Vignali DA. T(reg) stability: to be or not to be. Curr Opin Immunol 2016;39:39-43.   DOI
25 Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012;37:785-99.   DOI
26 Masteller EL, Tang Q, Bluestone JA. Antigen-specific regulatory T cells--ex vivo expansion and therapeutic potential. Semin Immunol 2006;18:103-10.   DOI
27 Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009;30:636-45.   DOI
28 Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. Regulatory T-cells in autoimmune diseases: challenges, controversies and--yet--unanswered questions. Autoimmun Rev 2015;14:105-16.   DOI
29 Schneider A, Buckner JH. Assessment of suppressive capacity by human regulatory T cells using a reproducible, bi-directional CFSE-based in vitro assay. Methods Mol Biol 2011;707:233-41.
30 Boks MA, Zwaginga JJ, van Ham SM, ten Brinke A. An optimized CFSE-based T-cell suppression assay to evaluate the suppressive capacity of regulatory T-cells induced by human tolerogenic dendritic cells. Scand J Immunol 2010;72:158-68.   DOI
31 Brusko TM, Koya RC, Zhu S, Lee MR, Putnam AL, McClymont SA, et al. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. PLoS One 2010;5:e11726.   DOI
32 Venken K, Thewissen M, Hellings N, Somers V, Hensen K, Rummens JL, et al. A CFSE based assay for measuring CD4+CD25+ regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses. J Immunol Methods 2007;322:1-11.   DOI
33 Raker VK, Domogalla MP, Steinbrink K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front Immunol 2015;6:569.
34 Trzonkowski P, Bacchetta R, Battaglia M, Berglund D, Bohnenkamp HR, ten Brinke A, et al. Hurdles in therapy with regulatory T cells. Sci Transl Med 2015;7:304ps18.   DOI
35 Gratz IK, Campbell DJ. Organ-specific and memory Treg cells: specificity, development, function, and maintenance. Front Immunol 2014;5:333.
36 Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest 2013;123:939-44.   DOI
37 Keijzer C, Wieten L, van Herwijnen M, van der Zee R, Van Eden W, Broere F. Heat shock proteins are therapeutic targets in autoimmune diseases and other chronic inflammatory conditions. Expert Opin Ther Targets 2012;16:849-57.   DOI
38 Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 2005;52:2212-21.   DOI
39 Vercoulen Y, van Teijlingen NH, de Kleer IM, Kamphuis S, Albani S, Prakken BJ. Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new? Arthritis Res Ther 2009;11:231-40.   DOI
40 Rodriguez-Palmero M, Franch A, Castell M, Pelegri C, Perez-Cano FJ, Kleinschnitz C, et al. Effective treatment of adjuvant arthritis with a stimulatory CD28-specific monoclonal antibody. J Rheumatol 2006;33:110-8.