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Regulatory T Cells: Promises and Challenges

  • Immunology (R Fairchild, Section Editor)
  • Published:
Current Transplantation Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Soon after their discovery in 1972, regulatory T cells (Tregs) appeared as nature’s gift to induce tolerance in auto- and alloimmune settings. We review here the barriers to the use of these bona fide cells and the strategies implanted to overcome them.

Recent Findings

Tregs are extremely rare and heterogenous, rendering them difficult to isolate and expand in vitro. Furthermore, their adoptive transfer was hurdled by their phenotypic instability and lack of intrinsic survival signals. Most studies in the field have focused on identifying distinctive Tregs markers for their pure isolation. This has also led to the discovery of different subtypes within this regulatory population, such as TR1 cells and CD8 + Tregs. In parallel, a myriad of techniques has been implanted for the targeted delivery of IL-2 as well as the bioengineering of Tregs with antigen-specific chimeric antigen receptors.

Summary

Despite the drawbacks of the use of Tregs, strategies based on targeted delivery of IL-2 and hijacking conventional CD4 cells into suppressive cells are emerging as a promising tool in the field of transplantation. However, more studies are still required, as the long-term safety and stability of these bioengineered cells remain under investigation.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.

    Article  CAS  PubMed  Google Scholar 

  2. Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J Immunol. 1972;108:586.

    CAS  PubMed  Google Scholar 

  3. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151.

    CAS  PubMed  Google Scholar 

  4. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–1.

    Article  CAS  PubMed  Google Scholar 

  5. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova J-L, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18–20.

    Article  CAS  PubMed  Google Scholar 

  6. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor \textlessem\textgreaterFoxp3\textless/em\textgreater. Science. 2003;299:1057–61.

    Article  CAS  PubMed  Google Scholar 

  7. Khattri R, Cox T, Yasayko S-A, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337–42.

    Article  CAS  PubMed  Google Scholar 

  8. van der Vliet HJJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol Hindawi Publishing Corporation. 2007;2007:89017.

    Google Scholar 

  9. Kitoh A, Ono M, Naoe Y, Ohkura N, Yamaguchi T, Yaguchi H, et al. Indispensable role of the Runx1-Cbfβ transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. Immunity. 2009;31:609–20.

    Article  CAS  PubMed  Google Scholar 

  10. Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio C-WJ, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008;28:112–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.

    Article  CAS  PubMed  Google Scholar 

  12. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8.

    Article  PubMed  CAS  Google Scholar 

  13. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, et al. Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes care. 2012/06/20. Am Diabetes Assoc. 2012;35:1817–20.

    Google Scholar 

  14. Marek-Trzonkowska N, Myśliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juścińska J, et al. Therapy of type 1 diabetes with CD4+CD25highCD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin Immunol Academic Press Inc. 2014;153:23–30.

    CAS  Google Scholar 

  15. Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol. 2009;133:22–6.

    Article  CAS  PubMed  Google Scholar 

  16. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117:1061–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martínez-Llordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009;10:1000–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Golab K, Leveson-Gower D, Wang XJ, Grzanka J, Marek-Trzonkowska N, Krzystyniak A, et al. Challenges in cryopreservation of regulatory T cells (Tregs) for clinical therapeutic applications. Int Immunopharmacol. 2013;16:371–5.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Hornero RA, Betts GJ, Sawitzki B, Vogt K, Harden PN, Wood KJ. CD45RA distinguishes CD4+CD25+CD127−/low TSDR demethylated regulatory T cell subpopulations with differential stability and susceptibility to tacrolimus-mediated inhibition of suppression. Transplantation. 2017;101:302–9.

  21. Wong J, Obst R, Correia-Neves M, Losyev G, Mathis D, Benoist C. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4\textlesssup\textgreater+\textless/sup\textgreater T cells. J Immunol. 2007;178:7032–41.

    Article  CAS  PubMed  Google Scholar 

  22. Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells. J Exp Med. 2006;203:1701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kleinewietfeld M, Starke M, Mitri DD, Borsellino G, Battistini L, Rö O, et al. CD49d provides access to “untouched” human Foxp3 Treg free of contaminating effector cells. Blood. 2009;113(4):827–36.

  24. Canavan JB, Scottà C, Vossenkämper A, Goldberg R, Elder MJ, Shoval I, et al. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn’s disease. Gut BMJ Publishing Group. 2016;65:584–94.

    CAS  Google Scholar 

  25. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity Cell Press. 2005;22:329–41.

    CAS  Google Scholar 

  26. Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8:351–8.

    Article  CAS  PubMed  Google Scholar 

  27. Mantel P-Y, Ouaked N, Rückert B, Karagiannidis C, Welz R, Blaser K, et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol. 2006;176:3593–602.

    Article  CAS  PubMed  Google Scholar 

  28. Long M, Park SG, Strickland I, Hayden MS, Ghosh S. Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity. 2009;31:921–31.

    Article  CAS  PubMed  Google Scholar 

  29. Molinero LL, Yang J, Gajewski T, Abraham C, Farrar MA, Alegre M-L. CARMA1 controls an early checkpoint in the thymic development of FoxP3\textlesssup\textgreater+\textless/sup\textgreater regulatory T cells. J Immunol. 2009;182:6736–43.

    Article  CAS  PubMed  Google Scholar 

  30. Ruan Q, Kameswaran V, Tone Y, Li L, Liou H-C, Greene MI, et al. Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity. 2009;31:932–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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;463:808–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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, The Rockefeller University Press. 2005;201:1061–7.

    CAS  Google Scholar 

  33. Li MO, Sanjabi S, Flavell RAA. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25:455–71.

    Article  CAS  PubMed  Google Scholar 

  34. Bayer AL, Yu A, Malek TR. Function of the IL-2R for thymic and peripheral CD4\textlesssup\textgreater+\textless/sup\textgreaterCD25\textlesssup\textgreater+\textless/sup\textgreater Foxp3\textlesssup\textgreater+\textless/sup\textgreater T regulatory cells. J Immunol. 2007;178:4062–71.

    Article  CAS  PubMed  Google Scholar 

  35. Liston A, Gray DHD. Homeostatic control of regulatory T cell diversity. 2014;14(3):154–65.

  36. Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity Cell Press. 2014;41:722–36.

    CAS  Google Scholar 

  37. Schmidt AM, Lu W, Sindhava VJ, Huang Y, Burkhardt JK, Yang E, et al. Regulatory T cells require TCR signaling for their suppressive function. J Immunol. 2015;194:4362–70.

    Article  CAS  PubMed  Google Scholar 

  38. Golovina TN, Mikheeva T, Suhoski MM, Aqui NA, Tai VC, Shan X, et al. CD28 costimulation is essential for human T regulatory expansion and function. J Immunol (Baltimore, Md : 1950). 2008;181:2855–68.

    Article  CAS  Google Scholar 

  39. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. 2011;11(2):119–30.

  40. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity. 2009;30:616–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 Investig American Society for Clinical Investigation; 2005;115:1923–1933.

  42. Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol. 2008;9:194–202.

    Article  CAS  PubMed  Google Scholar 

  43. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012;482:395–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med The Rockefeller University Press. 2007;204:1765–74.

    CAS  Google Scholar 

  46. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal T\textlesssub\textgreaterH\textless/sub\textgreater17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–60.

    Article  CAS  PubMed  Google Scholar 

  47. Round JL, O’Connell RM, Mazmanian SK. Coordination of tolerogenic immune responses by the commensal microbiota. J Autoimmun. 2010;34:J220–5.

    Article  CAS  PubMed  Google Scholar 

  48. 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 Treg cells via retinoic acid. J Exp Med The Rockefeller University Press. 2007;204:1775–85.

    CAS  Google Scholar 

  49. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500:232–6.

    Article  CAS  PubMed  Google Scholar 

  50. Soroosh P, Doherty TA, Duan W, Mehta AK, Choi H, Adams YF, et al. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J Exp Med The Rockefeller University Press. 2013;210:775–88.

    CAS  Google Scholar 

  51. Denning TL, Wang Y, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. Nat Immunol. 2007;8:1086–94.

    Article  CAS  PubMed  Google Scholar 

  52. Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, 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-beta and retinoic acid-dependent mechanism. J Exp Med The Rockefeller University Press. 2007;204:1757–64.

    CAS  Google Scholar 

  53. Sakaguchi S, Vignali DAA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. 2013;13(6):461–7.

  54. •• Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19:739–46 First paper identifying a distinct phenotype for TR1 cells allowing for their isolation.

    Article  CAS  PubMed  Google Scholar 

  55. •• Locafaro G, Andolfi G, Russo F, Cesana L, Spinelli A, Camisa B, et al. IL-10-engineered human CD4+ Tr1 cells eliminate myeloid leukemia in an HLA class I-dependent mechanism. Mol Ther Cell Press. 2017;25:2254–69 Novel paper describing for the first time the successful generation of TR1 cells by viral transduction and demonstrating the suppressive capacity of these engineered cells.

    CAS  Google Scholar 

  56. Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, et al. LAG-3 expression defines a subset of CD4 regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184:6545–51.

    Article  CAS  PubMed  Google Scholar 

  57. Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, et al. LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity Cell Press; 2018;49:120–133.e9.

  58. Roncarolo MG, Gregori S, Bacchetta R, Battaglia M. Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr Topics Microbiol Immunol Springer Verlag. 2014;380:39–68.

    CAS  Google Scholar 

  59. Brockmann L, Gagliani N, Steglich B, Giannou AD, Kempski J, Pelczar P, et al. IL-10 receptor signaling is essential for Tr1 cell function in vivo. J Immunol. 2017;198:1130–41.

    Article  CAS  PubMed  Google Scholar 

  60. Pot C, Jin H, Awasthi A, Liu SM, Lai C-Y, Madan R, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009;183:797–801.

    Article  CAS  PubMed  Google Scholar 

  61. Jofra T, Di Fonte R, Galvani G, Kuka M, Iannacone M, Battaglia M, et al. Tr1 cell immunotherapy promotes transplant tolerance via de novo Tr1 cell induction in mice and is safe and effective during acute viral infection. Eur J Immunol John Wiley & sons Ltd. 2018;48:1389–99.

    CAS  Google Scholar 

  62. Bacchetta R, Lucarelli B, Sartirana C, Gregori S, Lupo Stanghellini MT, Miqueu P, et al. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol Frontiers Media SA. 2014;5:16.

    Google Scholar 

  63. Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, et al. An essential role for the IL-2 receptor in Treg cell function. Nat Immunol Nature Publishing Group. 2016;17:1322–33.

    Article  CAS  Google Scholar 

  64. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy: Nature Publishing Group. 2017;27(1):109–18

  65. Pierson W, Cauwe B, Policheni A, Schlenner SM, Franckaert D, Berges J, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells. Nat Immunol. 2013;14:959–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ducloux D, Courivaud C, Bamoulid J, Vivet B, Chabroux A, Deschamps M, et al. Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation. J Am Soc Nephrol: JASN American Society of Nephrology. 2010;21:868–75.

    Article  CAS  Google Scholar 

  67. Shevach EM. Application of IL-2 therapy to target T regulatory cell function. 2012;33(12):626–32.

  68. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. 2012;12(3):180–90.

  69. Ballesteros-Tato A. Beyond regulatory T cells: the potential role for IL-2 to deplete T-follicular helper cells and treat autoimmune diseases: Future Medicine Ltd. 2014;6(11):1207–20.

  70. Zorn E, Mohseni M, Kim H, Porcheray F, Lynch A, Bellucci R, et al. Combined CD4+ donor lymphocyte infusion and low-dose recombinant IL-2 expand FOXP3+ regulatory T cells following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:382–8.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol Lancet Publishing Group. 2013;1:295–305.

    Article  CAS  Google Scholar 

  72. Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, et al. In vivo expansion of t reg cells with il-2-mab complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med. 2009;206:751–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Masteller EL, Warner MR, Ferlin W, Judkowski V, Wilson D, Glaichenhaus N, et al. Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes. J Immunol The American Association of Immunologists. 2003;171:5587–95.

    CAS  Google Scholar 

  74. Zuo L, Cullen CM, DeLay ML, Thornton S, Myers LK, Rosloniec EF, et al. A single-chain class II MHC-IgG3 fusion protein inhibits autoimmune arthritis by induction of antigen-specific Hyporesponsiveness. J Immunol The American Association of Immunologists. 2002;168:2554–9.

    CAS  Google Scholar 

  75. Li L, Yi Z, Wang B, Tisch R. Suppression of ongoing T cell-mediated autoimmunity by peptide-MHC class II dimer vaccination. J Immunol The American Association of Immunologists. 2009;183:4809–16.

    CAS  Google Scholar 

  76. •• Izquierdo C, Ortiz AZ, Presa M, Malo S, Montoya A, Garabatos N, et al. Treatment of T1D via optimized expansion of antigen-specific Tregs induced by IL-2/anti-IL-2 monoclonal antibody complexes and peptide/MHC tetramers. Sci Rep Nature publishing group. 2018;8(1):8106. Novel paper describing the combination of two previously known therapeutic modality for the targeted in-vio expansion and survival of antigen-specific Tregs.

  77. 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 American Association for the Advancement of Science. 2016;351:711–4.

    Article  CAS  Google Scholar 

  78. Bell CJM, Sun Y, Nowak UM, Clark J, Howlett S, Pekalski ML, et al. Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. J Autoimmun Academic Press. 2015;56:66–80.

    Article  CAS  Google Scholar 

  79. Hsieh WC, Hsu TS, Chang YJ, Lai MZ. IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells. Nat Commun Nature Publishing Group. 2018;9(1):463.

  80. Eskandari SK, Melo MB, Sulkaj I, Li N, Cai S, Allos H, et al. Engineering regulatory T cells with TCR-signaling-responsive interleukin 2 nanoparticles provides in situ suppression Of alloimmunity. Am J Transplant [Internet]. 2019;19 (suppl 3). https://atcmeetingabstracts.com/abstract/engineering-regulatory-t-cells-with-tcr-signaling-responsive-interleukin-2-nanoparticles-provides-in-situ-suppression-of-alloimmunity/. Accessed 25 Aug 2020.

  81. Green DR, Droin N, Pinkoski M. Activation-induced cell death in T cells. Immunol Rev. 2003;193:70–81.

  82. Weiss E-M, Schmidt A, Vobis D, Garbi N, Lahl K, Mayer CT, et al. Foxp3-mediated suppression of CD95L expression confers resistance to activation-induced cell death in regulatory T cells. J Immunol The American Association of Immunologists. 2011;187:1684–91.

    CAS  Google Scholar 

  83. •• Sula Karreci E, Eskandari SK, Dotiwala F, Routray SK, Kurdi AT, Assaker JP, et al. Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation. JCI Insight. 2017;2(21):e91599. Novel paper describing the leakage of granzyme B for the granules of activated Tregs leading to self-indfliced death.

  84. Azzi J, Skartsis N, Mounayar M, Magee CN, Batal I, Ting C, et al. Serine protease inhibitor 6 plays a critical role in protecting murine granzyme B-producing regulatory T cells. J Immunol (Baltimore, Md : 1950). 2013;191:2319–27.

    Article  CAS  Google Scholar 

  85. Efimova OV, Kelley TW. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol. 2009;10:59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Battaglia M, Stabilini A, Tresoldi E. Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol. 2012;821:279–93.

    Article  CAS  PubMed  Google Scholar 

  87. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells [Internet]. Available from: www.ScienceTranslationalMedicine.org. Accessed 17 May 2020.

  88. Adair PR, Kim YC, Zhang AH, Yoon J, Scott DW. Human Tregs made antigen specific by gene modification: the power to treat autoimmunity and antidrug antibodies with precision: Frontiers Media S.A. 2017;8:1117.

  89. Nijagal A, Derderian C, Le T, Jarvis E, Nguyen L, Tang Q, et al. Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice. Blood American Society of Hematology. 2013;121:4595–602.

    CAS  Google Scholar 

  90. Veerapathran A, Pidala J, Beato F, Yu X-Z, Anasetti C. Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood. 2011;118(20):5671–80.

  91. Tsang JYS, Tanriver Y, Jiang S, Xue SA, Ratnasothy K, Chen D, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J Clin Investig. 2008;118:3619–28.

    Article  PubMed  PubMed Central  Google Scholar 

  92. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Wright GP, Notley CA, Xue SA, Bendle GM, Holler A, Schumacher TN, et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci U S A. 2009;106(45):19078–83.

  94. Zhang Q, Lu W, Liang CL, Chen Y, Liu H, Qiu F, et al. Chimeric antigen receptor (CAR) Treg: a promising approach to inducing immunological tolerance. Frontiers Media S.A. 2018;9:2359.

  95. •• KG MD, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Investig American Society for Clinical Investigation. 2016;126:1413–24 Novel paper describing the generation of Tregs bearing an antigen specific chimeric antigen receptor allowing for direct Tregs activation.

    Article  Google Scholar 

  96. Ellis JM, Henson V, Slack R, Ng J, Hartzman RJ, Hurley CK. Frequencies of HLA-A2 alleles in five U.S. population groups predominance of A*02011 and identification of HLA-A*0231. Hum Immunol. 2000;61(3):334–40.

  97. Koristka S, Kegler A, Bergmann R, Arndt C, Feldmann A, Albert S, et al. Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology. J Autoimmun Academic Press. 2018;90:116–31.

    Article  CAS  Google Scholar 

  98. Noyan F, Zimmermann K, Hardtke-Wolenski M, Knoefel A, Schulde E, Geffers R, et al. Prevention of allograft rejection by use of regulatory T cells with an MHC-specific chimeric antigen receptor. Am J Transplant Blackwell Publishing Ltd. 2017;17:917–30.

    CAS  Google Scholar 

  99. Elinav E, Waks T, Eshhar Z. Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice. Gastroenterology WB Saunders. 2008;134:2014–24.

    Article  Google Scholar 

  100. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med Nature Publishing Group. 2015;21:581–90.

    Article  CAS  Google Scholar 

  101. Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI. 2019;5(8):e126194.

  102. McGovern JL, Wright GP, Stauss HJ. Engineering specificity and function of therapeutic regulatory T cells. Front Immunol. 2017;8:1517.

  103. Nigam P, Velu V, Kannanganat S, Chennareddi L, Kwa S, Siddiqui M, et al. Expansion of FOXP3 + CD8 T cells with suppressive potential in colorectal mucosa following a pathogenic simian immunodeficiency virus infection correlates with diminished antiviral T cell response and viral control. J Immunol The American Association of Immunologists. 2010;184:1690–701.

    CAS  Google Scholar 

  104. Churlaud G, Pitoiset F, Jebbawi F, Lorenzon R, Bellier B, Rosenzwajg M, et al. Human and mouse CD8+CD25+FOXP3+ regulatory T cells at steady state and during interleukin-2 therapy. Front Immunol. 2015;6:171.

  105. Zhang S, Wu M, Wang F. Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy. Cell Mole Immunol Chinese Soc Immunology. 2018;15:805–7.

    Article  CAS  Google Scholar 

  106. Yu Y, Ma X, Gong R, Zhu J, Wei L, Yao J. Recent advances in CD8+ regulatory T cell research. Oncol Lett. 2018;15(6):8187–94.

  107. Varthaman A, Clement M, Khallou-Laschet J, Fornasa G, Gaston AT, Dussiot M, et al. Physiological induction of regulatory Qa-1-restricted CD8+ T cells triggered by endogenous CD4+ T cell responses. PLoS One. 2011;6:e21628.

  108. Lu L, Kim H-J, Werneck MBF, Cantor H. Regulation of CD8 regulatory T cells: interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc Natl Acad Sci U S A. 2008;105(49):19420–5.

  109. Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004;5:516–23.

    Article  CAS  PubMed  Google Scholar 

  110. Stocks BT, Wilson CS, Marshall AF, Brewer LA, Moore DJ. Host expression of the CD8 Treg/NK cell restriction element Qa-1 is dispensable for transplant tolerance. Sci Rep. 2017;7(1):11181.

  111. Choi JY, Eskandari SK, Cai S, Sulkaj I, Assaker JP, Allos H, et al. Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts. Proc Natl Acad Sci U S A. 2020;117(11):6042–6.

  112. •• Bézie S, Charreau B, Vimond N, Lasselin J, Gérard N, Nerrière-Daguin V, et al. Human CD8+ Tregs expressing a MHC-specific CAR display enhanced suppression of human skin rejection and GVHD in NSG mice. Blood Adv. 2019;3:3522–38 First paper describing the generation of antigen-specific CD8+ Tregs via viral transduction, and demonstrating their ability in suppression allo-immunity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Author notes

  1. Juliano AlHaddad and Gandolina Melhem contributed equally to this work.

Authors and Affiliations

  1. Transplantation Research Center, Renal Division, Brigham and Women’s Hospital , Harvard Medical School, 221 Longwood Ave, Boston, MA, 02115, USA

    Juliano AlHaddad, Gandolina Melhem, Hazim Allos & Jamil Azzi

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  1. Juliano AlHaddad
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  2. Gandolina Melhem
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  3. Hazim Allos
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  4. Jamil Azzi
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Correspondence to Jamil Azzi.

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AlHaddad, J., Melhem, G., Allos, H. et al. Regulatory T Cells: Promises and Challenges. Curr Transpl Rep 7, 291–300 (2020). https://doi.org/10.1007/s40472-020-00292-0

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