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Volume 49 Issue 7
Jul.  2022
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Article Navigation >  Journal of Genetics and Genomics  > 2022  >  49(7): 599-611

Current status and perspectives of regulatory T cell-based therapy

doi: 10.1016/j.jgg.2022.05.005
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    a Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China;

  •  

    b Shanghai Affinity Biopharmaceutical Co., Ltd., 781 Cailun Road, Shanghai 201203, China;

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    c Unit of Immune and Metabolic Regulation, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

Funds:

Shanghai Collaborative Innovation Center of Cellular Homeostasis Regulation and Human Diseases

The National Key Research and Development Project (2019YFA0906102)

Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20210601). Figures are created with BioRender.com.

This research is supported by National Science Foundation for Distinguished Young Scholars (31525008)

National Natural Science Foundation of China (32130041, 81830051, 31961133011)

Shanghai Jiao Tong University (SJTU) - The Chinese University of Hong Kong (CUHK) Joint Research Collaboration Fund and the Fundamental Research Funds for Central Universities

  • Received Date: 2022-03-03
  • Accepted Date: 2022-05-18
  • Rev Recd Date: 2022-05-08
  • Publish Date: 2022-05-28
    Abstract
  • The CD4+FOXP3+ regulatory T (Treg) cells are essential for maintaining immune homeostasis in healthy individuals. Results from clinical trials of Treg cell-based therapies in patients with graft versus host disease (GVHD), type 1 diabetes (T1D), liver transplantation, and kidney transplantation have demonstrated that adoptive transfer of Treg cells is emerging as a promising strategy to promote immune tolerance. Here we provide an overview of recent progresses and current challenges of Treg cell-based therapies. We summarize the completed and ongoing clinical trials with human Treg cells. Notably, a few of the chimeric antigen receptor (CAR)-Treg cell therapies are currently undergoing clinical trials. Meanwhile, we describe the new strategies for engineering Treg cells used in preclinical studies. Finally, we envision that the use of novel synthetic receptors, metabolic regulators, combined therapies, and in vivo generated antigen-specific or engineered Treg cells through the delivery of modified mRNA and CRISPR-based gene editing will further promote the advances of next-generation Treg cell therapies.
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  • Abdeladhim, M., Zhang, A.H., Kropp, L.E., Lindrose, A.R., Venkatesha, S.H., Mitre, E., Scott, D.W., 2019. Engineered ovalbumin-expressing regulatory T cells protect against anaphylaxis in ovalbumin-sensitized mice. Clin. Immunol. 207, 49-54
    Akkaya, B., Oya, Y., Akkaya, M., Al Souz, J., Holstein, A.H., Kamenyeva, O., Kabat, J., Matsumura, R., Dorward, D.W., Glass, D.D., Shevach, E.M., 2019. Regulatory T cells mediate specific suppression by depleting peptide-MHC class II from dendritic cells. Nat. Immunol. 20, 218-231
    Ali, N., Zirak, B., Rodriguez, R.S., Pauli, M.L., Truong, H.A., Lai, K., Ahn, R., Corbin, K., Lowe, M.M., Scharschmidt, T.C., et al., 2017. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119-1129
    Allard, B., Allard, D., Buisseret, L., Stagg, J., 2020. The adenosine pathway in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 611-629
    Arpaia, N., Green, J.A., Moltedo, B., Arvey, A., Hemmers, S., Yuan, S., Treuting, P.M., Rudensky, A.Y., 2015. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078-1089
    Arvey, A., van der Veeken, J., Plitas, G., Rich, S.S., Concannon, P., Rudensky, A.Y., 2015. Genetic and epigenetic variation in the lineage specification of regulatory T cells. Elife 4, e07571
    Ayyoub, M., Deknuydt, F., Raimbaud, I., Dousset, C., Leveque, L., Bioley, G., Valmori, D., 2009. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc. Natl. Acad. Sci. U.S.A. 106, 8635-8640
    Battaglia, M., Stabilini, A., Migliavacca, B., Horejs-Hoeck, J., Kaupper, T., Roncarolo, M.G., 2006. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177, 8338-8347
    Bennett, C.L., Christie, J., Ramsdell, F., Brunkow, M.E., Ferguson, P.J., Whitesell, L., Kelly, T.E., Saulsbury, F.T., Chance, P.F., Ochs, H.D., 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21
    Beriou, G., Costantino, C.M., Ashley, C.W., Yang, L., Kuchroo, V.K., Baecher-Allan, C., Hafler, D.A., 2009. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240-4249
    Blat, D., Zigmond, E., Alteber, Z., Waks, T., Eshhar, Z., 2014. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol. Ther. 22, 1018-1028
    Bluestone, J.A., Buckner, J.H., Fitch, M., Gitelman, S.E., Gupta, S., Hellerstein, M.K., Herold, K.C., Lares, A., Lee, M.R., Li, K., et al., 2015. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189
    Boardman, D.A., Philippeos, C., Fruhwirth, G.O., Ibrahim, M.A., Hannen, R.F., Cooper, D., Marelli-Berg, F.M., Watt, F.M., Lechler, R.I., Maher, J., et al., 2017. Expression of a chimeric antigen receptor specific for donor HLA Class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am. J. Transplant. 17, 931-943
    Bonelli, M., Savitskaya, A., von Dalwigk, K., Steiner, C.W., Aletaha, D., Smolen, J.S., Scheinecker, C., 2008. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int. Immunol. 20, 861-868
    Brunkow, M.E., Jeffery, E.W., Hjerrild, K.A., Paeper, B., Clark, L.B., Yasayko, S.A., Wilkinson, J.E., Galas, D., Ziegler, S.F., Ramsdell, F., 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68-73
    Brunstein, C.G., Miller, J.S., Cao, Q., McKenna, D.H., Hippen, K.L., Curtsinger, J., Defor, T., Levine, B.L., June, C.H., Rubinstein, P., et al., 2011. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood:safety profile and detection kinetics. Blood 117, 1061-1070
    Brunstein, C.G., Miller, J.S., McKenna, D.H., Hippen, K.L., DeFor, T.E., Sumstad, D., Curtsinger, J., Verneris, M.R., MacMillan, M.L., Levine, B.L., et al., 2016. Umbilical cord blood-derived T regulatory cells to prevent GVHD:kinetics, toxicity profile, and clinical effect. Blood 127, 1044-1051
    Burzyn, D., Kuswanto, W., Kolodin, D., Shadrach, J.L., Cerletti, M., Jang, Y., Sefik, E., Tan, T.G., Wagers, A.J., Benoist, C., Mathis, D., 2013. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282-1295
    Cao, X., Cai, S.F., Fehniger, T.A., Song, J., Collins, L.I., Piwnica-Worms, D.R., Ley, T.J., 2007. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635-646
    Caudy, A.A., Reddy, S.T., Chatila, T., Atkinson, J.P., Verbsky, J.W., 2007. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482-487
    Chatila, T.A., Blaeser, F., Ho, N., Lederman, H.M., Voulgaropoulos, C., Helms, C., Bowcock, A.M., 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106, R75-R81
    Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A., Weiner, H.L., 1994. Regulatory T cell clones induced by oral tolerance:suppression of autoimmune encephalomyelitis. Science 265, 1237-1240
    Chen, Z., Barbi, J., Bu, S., Yang, H.Y., Li, Z., Gao, Y., Jinasena, D., Fu, J., Lin, F., Chen, C., et al., 2013. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272-285
    Chinen, T., Kannan, A.K., Levine, A.G., Fan, X., Klein, U., Zheng, Y., Gasteiger, G., Feng, Y., Fontenot, J.D., Rudensky, A.Y., 2016. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322-1333
    Collison, L.W., Workman, C.J., Kuo, T.T., Boyd, K., Wang, Y., Vignali, K.M., Cross, R., Sehy, D., Blumberg, R.S., Vignali, D.A., 2007. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566-569
    Coombes, J.L., Siddiqui, K.R., Arancibia-Carcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., Powrie, F., 2007. 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. 204, 1757-1764
    Dawson, N.A.J., Rosado-Sanchez, I., Novakovsky, G.E., Fung, V.C.W., Huang, Q., McIver, E., Sun, G., Gillies, J., Speck, M., Orban, P.C., Mojibian, M., Levings, M.K., 2020. Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells. Sci. Transl. Med. 12, eaaz3866
    Deaglio, S., Dwyer, K.M., Gao, W., Friedman, D., Usheva, A., Erat, A., Chen, J.F., Enjyoji, K., Linden, J., Oukka, M., et al., 2007. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257-1265
    Dijke, I.E., Hoeppli, R.E., Ellis, T., Pearcey, J., Huang, Q., McMurchy, A.N., Boer, K., Peeters, A.M., Aubert, G., Larsen, I., et al., 2016. Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells. Am. J. Transplant. 16, 58-71
    Dominguez-Villar, M., Baecher-Allan, C.M., Hafler, D.A., 2011. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med. 17, 673-675
    Dominguez-Villar, M., Hafler, D.A., 2018. Regulatory T cells in autoimmune disease. Nat. Immunol. 19, 665-673
    Dong, S., Hiam-Galvez, K.J., Mowery, C.T., Herold, K.C., Gitelman, S.E., Esensten, J.H., Liu, W., Lares, A.P., Leinbach, A.S., Lee M et al., 2021. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight 6, e147474
    Elhanati, Y., Sethna, Z., Callan, C.G., Jr., Mora, T., Walczak, A.M., 2018. Predicting the spectrum of TCR repertoire sharing with a data-driven model of recombination. Immunol. Rev. 284, 167-179
    Elinav, E., Waks, T., Eshhar, Z., 2008. Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice. Gastroenterology 134, 2014-2024
    Ferreira, L.M.R., Muller, Y.D., Bluestone, J.A., Tang, Q., 2019. Next-generation regulatory T cell therapy. Nat. Rev. Drug Discov. 18, 749-769
    Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., Lee, J., Goldfine, A.B., Benoist, C., Shoelson, S., et al., 2009. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930-939
    Fontenot, J.D., Gavin, M.A., Rudensky, A.Y., 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330-336
    Fransson, M., Piras, E., Burman, J., Nilsson, B., Essand, M., Lu, B., Harris, R.A., Magnusson, P.U., Brittebo, E., Loskog, A.S., 2012. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J. Neuroinflammation 9, 112
    Friedmann-Morvinski, D., Bendavid, A., Waks, T., Schindler, D., Eshhar, Z., 2005. Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood 105, 3087-3093
    Fultang, L., Booth, S., Yogev, O., Martins da Costa, B., Tubb, V., Panetti, S., Stavrou, V., Scarpa, U., Jankevics, A., Lloyd, G., et al., 2020. Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood 136, 1155-1160
    Gao, Y., Tang, J., Chen, W., Li, Q., Nie, J., Lin, F., Wu, Q., Chen, Z., Gao, Z., Fan, H., et al., 2015. Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc. Natl. Acad. Sci. U.S.A. 112, E3246-E3254
    Gerriets, V.A., Kishton, R.J., Nichols, A.G., Macintyre, A.N., Inoue, M., Ilkayeva, O., Winter, P.S., Liu, X., Priyadharshini, B., Slawinska, M.E., et al., 2015. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194-207
    Gluckman, E., Broxmeyer, H.A., Auerbach, A.D., Friedman, H.S., Douglas, G.W., Devergie, A., Esperou, H., Thierry, D., Socie, G., Lehn, P., et al., 1989. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N. Engl. J. Med. 321, 1174-1178
    Gondek, D.C., Lu, L.F., Quezada, S.A., Sakaguchi, S., Noelle, R.J., 2005. Cutting edge:contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783-1786
    Gottschalk, R.A., Corse, E., Allison, J.P., 2012. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J. Immunol. 188, 976-980
    Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C., et al., 2002. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097-1101
    Grossman, W.J., Verbsky, J.W., Barchet, W., Colonna, M., Atkinson, J.P., Ley, T.J., 2004. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589-601
    Helsen, C.W., Hammill, J.A., Lau, V.W.C., Mwawasi, K.A., Afsahi, A., Bezverbnaya, K., Newhook, L., Hayes, D.L., Aarts, C., Bojovic, B., et al., 2018. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat. Commun. 9, 3049
    Hernandez-Lopez, R.A., Yu, W., Cabral, K.A., Creasey, O.A., Lopez Pazmino, M.D.P., Tonai, Y., De Guzman, A., Makela, A., Saksela, K., Gartner, Z.J., 2021. T cell circuits that sense antigen density with an ultrasensitive threshold. Science 371, 1166-1171
    Hippen, K.L., Merkel, S.C., Schirm, D.K., Nelson, C., Tennis, N.C., Riley, J.L., June, C.H., Miller, J.S., Wagner, J.E., Blazar, B.R., 2011. Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease. Am. J. Transplant. 11, 1148-1157
    Hombach, A.A., Kofler, D., Rappl, G., Abken, H., 2009. Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity. Gene Ther. 16, 1088-1096
    Hori, S., Nomura, T., Sakaguchi, S., 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061
    Hull, C.M., Nickolay, L.E., Estorninho, M., Richardson, M.W., Riley, J.L., Peakman, M., Maher, J., Tree, T.I., 2017. Generation of human islet-specific regulatory T cells by TCR gene transfer. J. Autoimmun. 79, 63-73
    Ito, M., Komai, K., Mise-Omata, S., Iizuka-Koga, M., Noguchi, Y., Kondo, T., Sakai, R., Matsuo, K., Nakayama, T., Yoshie, O., et al., 2019. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246-250
    Joetham, A., Takeda, K., Taube, C., Miyahara, N., Matsubara, S., Koya, T., Rha, Y.H., Dakhama, A., Gelfand, E.W., 2007. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J. Immunol. 178, 1433-1442
    Kempkes, R.W.M., Joosten, I., Koenen, H., He, X., 2019. Metabolic pathways involved in regulatory T cell functionality. Front. Immunol. 10, 2839
    Khattri, R., Cox, T., Yasayko, S.A., Ramsdell, F., 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337-342
    Kim, Y.C., Zhang, A.H., Su, Y., Rieder, S.A., Rossi, R.J., Ettinger, R.A., Pratt, K.P., Shevach, E.M., Scott, D.W., 2015. Engineered antigen-specific human regulatory T cells:immunosuppression of FVIII-specific T- and B-cell responses. Blood 125, 1107-1115
    Kim, Y.C., Zhang, A.H., Yoon, J., Culp, W.E., Lees, J.R., Wucherpfennig, K.W., Scott, D.W., 2018. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J. Autoimmun. 92, 77-86
    Kitz, A., de Marcken, M., Gautron, A.S., Mitrovic, M., Hafler, D.A., Dominguez-Villar, M., 2016. AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep. 17, 1169-1183
    Kluger, M.A., Luig, M., Wegscheid, C., Goerke, B., Paust, H.J., Brix, S.R., Yan, I., Mittrucker, H.W., Hagl, B., Renner, E.D., et al., 2014. Stat3 programs Th17-specific regulatory T cells to control GN. J. Am. Soc. Nephrol. 25, 1291-1302
    Kluger, M.A., Melderis, S., Nosko, A., Goerke, B., Luig, M., Meyer, M.C., Turner, J.E., Meyer-Schwesinger, C., Wegscheid, C., Tiegs, G., et al., 2016. Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int. 89, 158-166
    Kolodin, D., van Panhuys, N., Li, C., Magnuson, A.M., Cipolletta, D., Miller, C.M., Wagers, A., Germain, R.N., Benoist, C., Mathis, D., 2015. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metabol. 21, 543-557
    Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J.A., Takayanagi, H., 2014. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62-68
    Krienke, C., Kolb, L., Diken, E., Streuber, M., Kirchhoff, S., Bukur, T., Akilli-Ozturk, O., Kranz, L.M., Berger, H., Petschenka, J., et al., 2021. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145-153
    Kuehn, H.S., Ouyang, W., Lo, B., Deenick, E.K., Niemela, J.E., Avery, D.T., Schickel, J.N., Tran, D.Q., Stoddard, J., Zhang, Y., et al., 2014. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345, 23-1627
    Lamarthee, B., Marchal, A., Charbonnier, S., Blein, T., Leon, J., Martin, E., Rabaux, L., Vogt, K., Titeux, M., Delville, M., et al., 2021. Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction. Nat. Commun. 12, 6446
    Levitsky, J., Miller, J., Wang, E., Rosen, A., Flaa, C., Abecassis, M., Mathew, J., Tambur, A., 2009. Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents. Hum. Immunol. 70, 146-150
    Li, Y., Lu, Y., Lin, S.H., Li, N., Han, Y., Huang, Q., Zhao, Y., Xie, F., Guo, Y., Deng, B., et al., 2021. Insulin signaling establishes a developmental trajectory of adipose regulatory T cells. Nat. Immunol. 22, 1175-1185
    Liu, Y., Liu, G., Wang, J., Zheng, Z.Y., Jia, L., Rui, W., Huang, D., Zhou, Z.X., Zhou, L., Wu, X., et al., 2021. Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors. Sci. Transl. Med. 13, eabb5191
    Liu, W., Putnam, A.L., Xu-Yu, Z., Szot, G.L., Lee, M.R., Zhu, S., Gottlieb, P.A., Kapranov, P., Gingeras, T.R., Fazekas de St Groth, B., et al., 2006. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701-1711
    MacDonald, K.G., Dawson, N.A.J., Huang, Q., Dunne, J.V., Levings, M.K., Broady, R., 2015. Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J. Allergy Clin. Immunol. 135, 946-955
    MacDonald, K.G., Hoeppli, R.E., Huang, Q., Gillies, J., Luciani, D.S., Orban, P.C., Broady, R., Levings, M.K., 2016. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Invest. 126, 1413-1424
    Macintyre, A.N., Gerriets, V.A., Nichols, A.G., Michalek, R.D., Rudolph, M.C., Deoliveira, D., Anderson, S.M., Abel, E.D., Chen, B.J., Hale, L.P., et al., 2014. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metabol. 20, 61-72
    MacMillan, M.L., Hippen, K.L., McKenna, D.H., Kadidlo, D., Sumstad, D., DeFor, T.E., Brunstein, C.G., Holtan, S.G., Miller, J.S., Warlick, E.D., et al., 2021. First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings. Blood Adv. 5, 1425-1436
    McClymont, S.A., Putnam, A.L., Lee, M.R., Esensten, J.H., Liu, W., Hulme, M.A., Hoffmuller, U., Baron, U., Olek, S., Bluestone, J.A., et al., 2011. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186, 3918-3926
    Michalek, R.D., Gerriets, V.A., Jacobs, S.R., Macintyre, A.N., MacIver, N.J., Mason, E.F., Sullivan, S.A., Nichols, A.G., Rathmell, J.C., 2011. Cutting edge:distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299-3303
    Miyara, M., Gorochov, G., Ehrenstein, M., Musset, L., Sakaguchi, S., Amoura, Z., 2011. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun. Rev. 10, 744-755
    Morikawa, H., Ohkura, N., Vandenbon, A., Itoh, M., Nagao-Sato, S., Kawaji, H., Lassmann, T., Carninci, P., Hayashizaki, Y., Forrest, A.R., et al., 2014. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl. Acad. Sci. U.S.A. 111, 5289-5294
    Morsut, L., Roybal, K.T., Xiong, X., Gordley, R.M., Coyle, S.M., Thomson, M., Lim, W.A., 2016. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164, 780-791
    Nosbaum, A., Prevel, N., Truong, H.A., Mehta, P., Ettinger, M., Scharschmidt, T.C., Ali, N.H., Pauli, M.L., Abbas, A.K., Rosenblum, M.D., 2016. Cutting edge:regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010-2014
    Noval Rivas, M., Burton, O.T., Wise, P., Charbonnier, L.M., Georgiev, P., Oettgen, H.C., Rachid, R., Chatila, T.A., 2015. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42, 512-523
    O'Neill, L.A., Kishton, R.J., Rathmell, J., 2016. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553-565
    Noyan, F., Zimmermann, K., Hardtke-Wolenski, M., Knoefel, A., Schulde, E., Geffers, R., Hust, M., Huehn, J., Galla, M., Morgan, M., Jokuszies, A., Manns, M.P., Jaeckel, E., 2017. Prevention of allograft rejection by use of regulatory T cells with an MHC-specific chimeric antigen receptor. Am. J. Transplant. 17, 917-930
    Ohkura, N., Kitagawa, Y., Sakaguchi, S., 2013. Development and maintenance of regulatory T cells. Immunity 38, 414-423
    Onishi, Y., Fehervari, Z., Yamaguchi, T., Sakaguchi, S., 2008. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc. Natl. Acad. Sci. U.S.A. 105, 10113-10118
    Opstelten, R., de Kivit, S., Slot, M.C., van den Biggelaar, M., Iwaszkiewicz-Grzes, D., Gliwinski, M., Scott, A.M., Blom, B., Trzonkowski, P., Borst, J., et al., 2020. GPA33:a marker to identify stable human regulatory T cells. J. Immunol. 204, 3139-3148
    Ouyang, W., Liao, W., Luo, C.T., Yin, N., Huse, M., Kim, M.V., Peng, M., Chan, P., Ma, Q., Mo, Y., et al., 2012. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 491, 554-559
    Pandiyan, P., Zheng, L., Ishihara, S., Reed, J., Lenardo, M.J., 2007. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8, 1353-1362
    Panduro, M., Benoist, C., Mathis, D., 2016. Tissue Tregs. Annu. Rev. Immunol. 34, 609-633
    Passerini, L., Rossi Mel, E., Sartirana, C., Fousteri, G., Bondanza, A., Naldini, L., Roncarolo, M.G., Bacchetta, R., 2013. CD4(+) T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci. Transl. Med. 5, 215ra174
    Pierini, A., Ruggeri, L., Carotti, A., Falzetti, F., Saldi, S., Terenzi, A., Zucchetti, C., Ingrosso, G., Zei, T., Iacucci Ostini, R., et al., 2021. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia. Blood Adv. 5, 1199-1208
    Pompura, S.L., Dominguez-Villar, M., 2018. The PI3K/AKT signaling pathway in regulatory T-cell development, stability, and function. J. Leukoc. Biol. 103,1065-1076
    Powell, B.R., Buist, N.R., Stenzel, P., 1982. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J. Pediatr. 100, 731-737
    Puccetti, P., Grohmann, U., 2007. Ido and regulatory T cells:a role for reverse signalling and non-canonical NF-kappaB activation. Nat. Rev. Immunol. 7, 817-823
    Raffin, C., Vo, L.T., Bluestone, J.A., 2020. Treg cell-based therapies:challenges and perspectives. Nat. Rev. Immunol. 20, 158-172
    Raffin, C., Zhou, Y., Piccoli, L., Lanzavecchia, A., Sadelain, M., Tareen, S.U., Fontenot, J.D., Bluestone, J.A., 2018. Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis. J. Immunol. 200. (Suppl. 1),176.17
    Rafiq, S., Hackett, C.S., Brentjens, R.J., 2020. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147-167
    Rana, J., Perry, D.J., Kumar, S.R.P., Munoz-Melero, M., Saboungi, R., Brusko, T.M., Biswas, M., 2021. CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII. Mol. Ther. 29, 2660-2676
    Roemhild, A., Otto, N.M., Moll, G., Abou-El-Enein, M., Kaiser, D., Bold, G., Schachtner, T., Choi, M., Oellinger, R., Landwehr-Kenzel, S., et al., 2020. Regulatory T cells for minimising immune suppression in kidney transplantation:phase I/IIa clinical trial. BMJ 371, m3734
    Roybal, K.T., Williams, J.Z., Morsut, L., Rupp, L.J., Kolinko, I., Choe, J.H., Walker, W.J., McNally, K.A., Lim, W.A., 2016. Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors. Cell 167, 419-432
    Rubtsov, Y.P., Rasmussen, J.P., Chi, E.Y., Fontenot, J., Castelli, L., Ye, X., Treuting, P., Siewe, L., Roers, A., Henderson, W.R. Jr., Muller, W., et al., 2008. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546-558
    Rurik, J.G., Tombacz, I., Yadegari, A., Mendez Fernandez, P.O., Shewale, S.V., Li, L., Kimura, T., Soliman, O.Y., Papp, T.E., Tam, Y.K., et al., 2022. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91-96
    Sakaguchi, S., Mikami, N., Wing, J.B., Tanaka, A., Ichiyama, K., Ohkura, N., 2020. Regulatory T cells and human disease. Annu. Rev. Immunol. 38, 541-566
    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., Toda, M., 1995. 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. 155, 1151-1164
    Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., 2009. Regulatory T cells:how do they suppress immune responses? Int. Immunol. 21, 1105-1111
    Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M., 2008. Regulatory T cells and immune tolerance. Cell 133, 775-787
    Samstein, R.M., Arvey, A., Josefowicz, S.Z., Peng, X., Reynolds, A., Sandstrom, R., Neph, S., Sabo, P., Kim, J.M., Liao, W., et al., 2012. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153-166
    Savage, P.A., Klawon, D.E.J., Miller, C.H., 2020. Regulatory T cell development. Annu. Rev. Immunol. 38, 421-453
    Sawitzki, B., Harden, P.N., Reinke, P., Moreau, A., Hutchinson, J.A., Game, D.S., Tang, Q., Guinan, E.C., Battaglia, M., Burlingham, W.J., et al., 2020. Regulatory cell therapy in kidney transplantation (The ONE Study):a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet 395, 1627-1639
    Schiering, C., Krausgruber, T., Chomka, A., Frohlich, A., Adelmann, K., Wohlfert, E.A., Pott, J., Griseri, T., Bollrath, J., Hegazy, A.N., et al., 2014. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564-568
    Schmidt, R., Steinhart, Z., Layeghi, M., Freimer, J.W., Bueno, R., Nguyen, V.Q., Blaeschke, F., Ye, C.J., Marson, A., 2022. CRISPR activation and interference screens decode stimulation responses in primary human T cells. Science 375, eabj4008
    Schubert, D., Bode, C., Kenefeck, R., Hou, T.Z., Wing, J.B., Kennedy, A., Bulashevska, A., Petersen, B.S., Schaffer, A.A., Gruning, B.A., et al., 2014. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410-1416
    Seay, H.R., Putnam, A.L., Cserny, J., Posgai, A.L., Rosenau, E.H., Wingard, J.R., Girard, K.F., Kraus, M., Lares, A.P., Brown, H.L., et al., 2017. Expansion of human Tregs from cryopreserved umbilical cord blood for GMP-compliant autologous adoptive cell transfer therapy. Mol. Ther. Methods Clin. Dev. 4, 178-191
    Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S.I., Nanan, R., et al., 2006. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693-1700
    Sefik, E., Geva-Zatorsky, N., Oh, S., Konnikova, L., Zemmour, D., McGuire, A.M., Burzyn, D., Ortiz-Lopez, A., Lobera, M., Yang, J., et al., 2015. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349, 993-997
    Shevach, E.M., Thornton, A.M., 2014. tTregs, pTregs, and iTregs:similarities and differences. Immunol. Rev. 259, 88-102
    Shi, L.Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D.R., Chi, H., 2011. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367-1376
    Shifrut, E., Carnevale, J., Tobin, V., Roth, T.L., Woo, J.M., Bui, C.T., Li, P.J., Diolaiti, M.E., Ashworth, A., Marson, A., 2018. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 175, 1958-1971
    Skuljec, J., Chmielewski, M., Happle, C., Habener, A., Busse, M., Abken, H., Hansen, G., 2017. Chimeric antigen receptor-redirected regulatory T cells suppress experimental allergic airway inflammation, a model of asthma. Front. Immunol. 8, 1125
    Song, Y., Wang, N., Chen, L., Fang, L., 2021. Tr1 cells as a key regulator for maintaining immune homeostasis in transplantation. Front. Immunol. 12, 671579
    Sprouse, M.L., Shevchenko, I., Scavuzzo, M.A., Joseph, F., Lee, T., Blum, S., Borowiak, M., Bettini, M.L., Bettini, M., 2018. Cutting edge:low-affinity TCRs support regulatory t cell function in autoimmunity. J. Immunol. 200, 909-914
    Sun, C.M., Hall, J.A., Blank, R.B., Bouladoux, N., Oukka, M., Mora, J.R., Belkaid, Y., 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775-1785
    Szurek, E., Cebula, A., Wojciech, L., Pietrzak, M., Rempala, G., Kisielow, P., Ignatowicz, L., 2015. Differences in expression level of helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4+Foxp3+ regulatory T cells. PLoS One 10, e0141161
    Tenspolde, M., Zimmermann, K., Weber, L.C., Hapke, M., Lieber, M., Dywicki, J., Frenzel, A., Hust, M., Galla, M., Buitrago-Molina, L.E., et al., 2019. Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. J. Autoimmun. 103, 102289
    Thornton, A.M., Korty, P.E., Tran, D.Q., Wohlfert, E.A., Murray, P.E., Belkaid, Y., Shevach, E.M., 2010. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433-3441
    Thornton, A.M., Shevach, E.M., 1998. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287-296
    Tsang, J.Y., Tanriver, Y., Jiang, S., Xue, S.A., Ratnasothy, K., Chen, D., Stauss, H.J., Bucy, R.P., Lombardi, G., Lechler, R., 2008. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J. Clin. Invest. 118, 3619-3628
    van Roon, J.A., Hartgring, S.A., van der Wurff-Jacobs, K.M., Bijlsma, J.W., Lafeber, F.P., 2010. Numbers of CD25+Foxp3+ T cells that lack the IL-7 receptor are increased intra-articularly and have impaired suppressive function in RA patients. Rheumatology 49, 2084-2089
    Voskens, C.J., Stoica, D., Roessner, S., Vitali, F., Zundler, S., Rosenberg, M., Wiesinger, M., Wunder, J., Siegmund, B., Schuler-Thurner, B., et al., 2021. Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01):protocol of a phase 1, open-label, fast-track dose-escalation clinical trial. BMJ Open 11, e049208
    Wagner, J.E., Kernan, N.A., Steinbuch, M., Broxmeyer, H.E., Gluckman, E., 1995. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet 346, 214-219
    Weiss, J.M., Bilate, A.M., Gobert, M., Ding, Y., Curotto de Lafaille, M.A., Parkhurst, C.N., Xiong, H., Dolpady, J., Frey, A.B., Ruocco, M.G., et al., 2012. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723-1742, S1721
    Wildin, R.S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al., 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18-20
    Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., Sakaguchi, S., 2008. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271-275
    Wright, G. P., Notley, C.A., Xue, S.A., Bendle, G.M., Holler, A., Schumacher, T.N., Ehrenstein, M.R., Stauss, H.J., 2009. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc. Natl. Acad. Sci. U.S.A. 106, 19078-19083
    Yadav, M., Louvet, C., Davini, D., Gardner, J.M., Martinez-Llordella, M., Bailey-Bucktrout, S., Anthony, B.A., Sverdrup, F.M., Head, R., Kuster, D.J., et al., 2012. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713-1722, S1711-1719
    Yang, B.H., Hagemann, S., Mamareli, P., Lauer, U., Hoffmann, U., Beckstette, M., Fohse, L., Prinz, I., Pezoldt, J., Suerbaum, S., et al., 2016. Foxp3+ T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444-457
    Zaiss, D.M., van Loosdregt, J., Gorlani, A., Bekker, C.P., Grone, A., Sibilia, M., van Bergen en Henegouwen, P.M., Roovers, R.C., Coffer, P.J., Sijts, A.J., 2013. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 38, 275-284
    Zhang, A.H., Yoon, J., Kim, Y.C., Scott, D.W., 2018. Targeting antigen-specific B cells using antigen-expressing transduced regulatory T cells. J. Immunol. 201, 1434-1441
    Zhang, B., Sun, J., Wang, Y., Ji, D., Yuan, Y., Li, S., Sun, Y., Hou, Y., Li, P., Zhao, L., et al., 2021. Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells. Nat. Biomed. Eng. 5, 1288-1305
    Zhou, X., Bailey-Bucktrout, S.L., Jeker, L.T., Penaranda, C., Martinez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., Bluestone, J.A., 2009. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000-1007
    Zhu, Y., Qian, Y., Li, Z., Li, Y., Li, B., 2021. Neoantigen-reactive T cell:an emerging role in adoptive cellular immunotherapy. MedComm 2, 207-220
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