The Tolerant Immune System: Biological Significance and Clinical Implications of T Cell Tolerance

Author(s): Thea Magrone*, Emilio Jirillo.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: T cell tolerance both at thymic and peripheral levels is a mechanism of protection finalized to eradicate autoreactive T cell clones and/or to maintain immune homeostasis, especially, postnatally. Central tolerance occurs in the thymic medulla via a mechanism of negative selection which leads to the eradication of autoreactive T cell clones.

Mechanisms of Action: Such a tolerogenic event relies on Fas-mediated apoptosis of autoreactive T cell clones operated by thymic dendritic cells (DCs), on the one hand. On the other hand, activated thymic T regulatory (Treg) cells in cooperation with medullary thymic epithelial cells and DCs suppress autoreactive T cell clones. Peripherally, different types of Treg cells exert the so-called peripheral tolerance towards autoreactive T cell clones which may have escaped from negative selection mechanisms. At the same time, peripheral Treg cells activated by tolerogenic DC have antiinflammatory activities, especially in the intestine towards food and microbial antigens.

Drug Targeting: Various natural and dietary products, such as vitamins (A, C, D), lactobacilli and polyphenols will be described for their tolerogenic capacity to attenuate the inflammatory pathway, as observed in preclinical and clinical studies.

Keywords: Dendritic cells, immune system, medullary thymic epithelial cells, natural products, thymus, T regulatory cells.

Ploegh, H. Machinery that guides immunity. Nature, 2017, 551(7681), 442-443.
Pancer, Z.; Cooper, M.D. The evolution of adaptive immunity. Annu. Rev. Immunol., 2006, 24, 497-518.
Marelli, G.; Sica, A.; Vannucci, L.; Allavena, P. Inflammation as target in cancer therapy. Curr. Opin. Pharmacol., 2017, 35, 57-65.
Mattner, J.; Wirtz, S. Friend or Foe? The ambiguous role of innate lymphoid cells in cancer development. Trends Immunol., 2017, 38(1), 29-38.
Balachandran, V.P.; Łuksza, M.; Zhao, J.N.; Balachandran, V.P.; Łuksza, M.; Zhao, J.N.; Makarov, V.; Moral, J.A.; Remark, R.; Herbst, B.; Askan, G.; Bhanot, U.; Senbabaoglu, Y.; Wells, D.K.; Cary, C.I.O.; Grbovic-Huezo, O.; Attiyeh, M.; Medina, B.; Zhang, J.; Loo, J.; Saglimbeni, J.; Abu-Akeel, M.; Zappasodi, R.; Riaz, N.; Smoragiewicz, M.; Kelley, Z.L.; Basturk, O. Australian Pancreatic Cancer Genome Initiative; Garvan Institute of Medical Research; Prince of Wales Hospital; Royal North Shore Hospital; University of Glasgow; St Vincent’s Hospital; QIMR Berghofer Medical Research Institute; University of Melbourne, Centre for Cancer Research; University of Queensland, Institute for Molecular Bioscience; Bankstown Hospital; Liverpool Hospital; Royal Prince Alfred Hospital, Chris O’Brien Lifehouse; Westmead Hospital; Fremantle Hospital; St John of God Healthcare; Royal Adelaide Hospital; Flinders Medical Centre; Envoi Pathology; Princess Alexandria Hospital; Austin Hospital; Johns Hopkins Medical Institutes; ARC-Net Centre for Applied Research on Cancer, Gönen, M.; Levine, A.J.; Allen, P.J.; Fearon, D.T.; Merad, M.; Gnjatic, S.; Iacobuzio-Donahue, C.A.; Wolchok, J.D.; DeMatteo, R.P.; Chan, T.A.; Greenbaum, B.D.; Merghoub, T.; Leach, S.D. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 2017, 551(7681), 512-516.
Łuksza, M.; Riaz, N.; Makarov, V.; Balachandran, V.P.; Hellmann, M.D.; Solovyov, A.; Rizvi, N.A.; Merghoub, T.; Levine, A.J.; Chan, T.A.; Wolchok, J.D.; Greenbaum, B.D. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature, 2017, 551(7681), 517-520.
Miller, J.F. The golden anniversary of the thymus. Nat. Rev. Immunol., 2011, 11(7), 489-495.
Davis, M.M.; Boniface, J.J.; Reich, Z.; Lyons, D.; Hampl, J.; Arden, B.; Chien, Y. Ligand recognition by alpha beta T cell receptors. Annu. Rev. Immunol., 1998, 16, 523-544.
Magrone, T.; Jirillo, E. Development and organization of the secondary and tertiary lymphoid organs: Influence of microbial and food antigens. Endocr. Metab. Immune Disord. Drug Targets, 2019, 19(2), 128-135.
Takada, K.; Takahama, Y. Positive-selection-inducing self-peptides displayed by cortical thymic epithelial cells. Adv. Immunol., 2015, 125, 87-110.
Anderson, G.; Takahama, Y. Thymic epithelial cells: Working class heroes for T cell development and repertoire selection. Trends Immunol., 2012, 33(6), 256-263.
Murata, S.; Sasaki, K.; Kishimoto, T.; Niwa, S.; Hayashi, H.; Takahama, Y.; Tanaka, K. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science, 2007, 316(5829), 1349-1353.
Lancaster, J.N.; Li, Y.; Ehrlich, L.I.R. Chemokine-mediated choreography of thymocyte development and selection. Trends Immunol., 2018, 39(2), 86-98.
Takaba, H.; Takayanagi, H. The mechanisms of T Cell selection in the thymus. Trends Immunol., 2017, 38(11), 805-816.
Alves, N.L.; Ribeiro, A.R. Thymus medulla under construction: Time and space oddities. Eur. J. Immunol., 2016, 46(4), 829-833.
Rodrigues, P.M.; Ribeiro, A.R.; Perrod, C.; Landry, J.J.M.; Araújo, L.; Pereira-Castro, I.; Benes, V.; Moreira, A.; Xavier-Ferreira, H.; Meireles, C.; Alves, N.L. Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood, 2017, 130(4), 478-488.
Muñoz-Fontela, C.; Mandinova, A.; Aaronson, S.A.; Lee, S.W. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat. Rev. Immunol., 2016, 16(12), 741-750.
Haljasorg, U.; Dooley, J.; Laan, M.; Kisand, K.; Bichele, R.; Liston, A.; Peterson, P. Irf4 Expression in thymic epithelium is critical for thymic regulatory t cell homeostasis. J. Immunol., 2017, 198(5), 1952-1960.
Rodrigues, P.M.; Peterson, P.; Alves, N.L. Setting up the perimeter of tolerance: Insights into mTEC physiology. Trends Immunol., 2018, 39(1), 2-5.
Akiyama, N.; Shinzawa, M.; Miyauchi, M.; Yanai, H.; Tateishi, R.; Shimo, Y.; Ohshima, D.; Matsuo, K.; Sasaki, I.; Hoshino, K.; Wu, G.; Yagi, S.; Inoue, J.; Kaisho, T.; Akiyama, T. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J. Exp. Med., 2014, 211(12), 2425-2438.
Hauri-Hohl, M.; Zuklys, S.; Holländer, G.A.; Ziegler, S.F. A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla. Nat. Immunol., 2014, 15(6), 554-561.
Satoh, R.; Kakugawa, K.; Yasuda, T.; Yoshida, H.; Sibilia, M.; Katsura, Y.; Levi, B.; Abramson, J.; Koseki, Y.; Koseki, H.; van Ewijk, W.; Hollander, G.A.; Kawamoto, H. Requirement of stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLoS Genet., 2016, 12(1)e1005776
Lomada, D.; Jain, M.; Bolner, M.; Reeh, K.A.; Kang, R.; Reddy, M.C.; DiGiovanni, J.; Richie, E.R. Stat3 signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet., 2010, 12(1)e1005777
Cosway, E.J.; Lucas, B.; James, K.D.; Parnell, S.M.; Carvalho-Gaspar, M.; White, A.J.; Tumanov, A.V.; Jenkinson, W.E.; Anderson, G. Redefining thymus medulla specialization for central tolerance. J. Exp. Med., 2017, 214(11), 3183-3195.
Gray, D.H.; Seach, N.; Ueno, T.; Milton, M.K.; Liston, A.; Lew, A.M.; Goodnow, C.C.; Boyd, R.L. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood, 2006, 108(12), 3777-3785.
Sansom, S.N.; Shikama-Dorn, N.; Zhanybekova, S.; Nusspaumer, G.; Macaulay, I.C.; Deadman, M.E.; Heger, A.; Ponting, C.P.; Holländer, G.A. Population and single-cell genomics reveal the aire dependency, relief from polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res., 2014, 24(12), 1918-1931.
Hubert, F.X.; Kinkel, S.A.; Davey, G.M.; Phipson, B.; Mueller, S.N.; Liston, A.; Proietto, A.I.; Cannon, P.Z.; Forehan, S.; Smyth, G.K.; Wu, L.; Goodnow, C.C.; Carbone, F.R.; Scott, H.S.; Heath, W.R. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood, 2011, 118(9), 2462-2472.
Perry, J.S.; Hsieh, C.S. Development of T-cell tolerance utilizes both cell-autonomous and cooperative presentation of self-antigen. Immunol. Rev., 2016, 271(1), 141-155.
DeVoss, J.; Hou, Y.; Johannes, K.; Lu, W.; Liou, G.I.; Rinn, J.; Chang, H.; Caspi, R.R.; Fong, L.; Anderson, M.S. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med., 2006, 203(12), 2727-2735.
Fan, Y.; Rudert, W.A.; Grupillo, M.; He, J.; Sisino, G.; Trucco, M. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J., 2009, 28(18), 2812-2824.
Yamano, T.; Nedjic, J.; Hinterberger, M.; Steinert, M.; Koser, S.; Pinto, S.; Gerdes, N.; Lutgens, E.; Ishimaru, N.; Busslinger, M.; Brors, B.; Kyewski, B.; Klein, L. Thymic B cells are licensed to present self antigens for central t cell tolerance induction. Immunity, 2015, 42(6), 1048-1061.
Perniola, R. Twenty years of aire. Front. Immunol., 2018, 9, 98.
DeVoss, J.J.; LeClair, N.P.; Hou, Y.; Grewal, N.K.; Johannes, K.P.; Lu, W.; Yang, T.; Meagher, C.; Fong, L.; Strauss, E.C.; Anderson, M.S. An autoimmune response to odorant binding protein 1a is associated with dry eye in the Aire-deficient mouse. J. Immunol., 2010, 184(8), 4236-4246.
Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet., 1997, 17(4), 399-403.
Nagamine, K.; Peterson, P.; Scott, H.S.; Kudoh, J.; Minoshima, S.; Heino, M.; Krohn, K.J.; Lalioti, M.D.; Mullis, P.E.; Antonarakis, S.E.; Kawasaki, K.; Asakawa, S.; Ito, F.; Shimizu, N. Positional cloning of the APECED gene. Nat. Genet., 1997, 17(4), 393-398.
Browne, S.K. Anticytokine autoantibody-associated immunodeficiency. Annu. Rev. Immunol., 2014, 32, 635-657.
Capalbo, D.; De Martino, L.; Giardino, G.; Di Mase, R.; Di Donato, I.; Parenti, G.; Vajro, P.; Pignata, C.; Salerno, M. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: insights into genotype-phenotype correlation. Int. J. Endocrinol., 2012, 2012353250
Meyer, S.; Woodward, M.; Hertel, C.; Vlaicu, P.; Haque, Y.; Kärner, J.; Macagno, A.; Onuoha, S.C.; Fishman, D.; Peterson, H.; Metsküla, K.; Uibo, R.; Jäntti, K.; Hokynar, K.; Wolff, A.S.B. APECED patient collaborative, Krohn, K.; Ranki, A.; Peterson, P.; Kisand, K.; Hayday, A.; Meloni, A.; Kluger, N.; Husebye, E.S.; Podkrajsek, K.T.; Battelino, T.; Bratanic, N.; Peet, A. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell, 2016, 166(3), 582-595.
Gardner, J.M.; Metzger, T.C.; McMahon, E.J.; Au-Yeung, B.B.; Krawisz, A.K.; Lu, W.; Price, J.D.; Johannes, K.P.; Satpathy, A.T.; Murphy, K.M.; Tarbell, K.V.; Weiss, A.; Anderson, M.S. Extrathymic aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4+ T cells. Immunity, 2013, 39(3), 560-572.
Guerau-de-Arellano, M.; Martinic, M.; Benoist, C.; Mathis, D. Neonatal tolerance revisited: A perinatal window for aire control of autoimmunity. J. Exp. Med., 2009, 206(6), 1245-1252.
Takaba, H.; Morishita, Y.; Tomofuji, Y.; Danks, L.; Nitta, T.; Komatsu, N.; Kodama, T.; Takayanagi, H. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell, 2015, 163(4), 975-987.
Sanders, S.J.; Murtha, M.T.; Gupta, A.R.; Murdoch, J.D.; Raubeson, M.J.; Willsey, A.J.; Ercan-Sencicek, A.G.; DiLullo, N.M.; Parikshak, N.N.; Stein, J.L.; Walker, M.F.; Ober, G.T.; Teran, N.A.; Song, Y.; El-Fishawy, P.; Murtha, R.C.; Choi, M.; Overton, J.D.; Bjornson, R.D.; Carriero, N.J.; Meyer, K.A.; Bilguvar, K.; Mane, S.M.; Sestan, N.; Lifton, R.P.; Günel, M.; Roeder, K.; Geschwind, D.H.; Devlin, B.; State, M.W. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 2012, 485(7397), 237-241.
Kwan, K.Y. Transcriptional dysregulation of neocortical circuit assembly in ASD. Int. Rev. Neurobiol., 2013, 113, 167-205.
Shu, X.S.; Li, L.; Ji, M.; Cheng, Y.; Ying, J.; Fan, Y.; Zhong, L.; Liu, X.; Tsao, S.W.; Chan, A.T.; Tao, Q. FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. Carcinogenesis, 2013, 34(9), 1984-1993.
Seach, N.; Ueno, T.; Fletcher, A.L.; Lowen, T.; Mattesich, M.; Engwerda, C.R.; Scott, H.S.; Ware, C.F.; Chidgey, A.P.; Gray, D.H.; Boyd, R.L. The lymphotoxin pathway regulates aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J. Immunol., 2008, 180(8), 5384-5392.
Li, J.; Park, J.; Foss, D.; Goldschneider, I. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med., 2009, 206(3), 607-622.
Proietto, A.I.; van Dommelen, S.; Zhou, P.; Rizzitelli, A.; D’Amico, A.; Steptoe, R.J.; Naik, S.H.; Lahoud, M.H.; Liu, Y.; Zheng, P.; Shortman, K.; Wu, L. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. USA, 2008, 105(50), 19869-19874.
Leventhal, D.S.; Gilmore, D.C.; Berger, J.M.; Nishi, S.; Lee, V.; Malchow, S.; Kline, D.E.; Kline, J.; Vander Griend, D.J.; Huang, H.; Socci, N.D.; Savage, P.A. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity, 2016, 44(4), 847-559.
Kroger, C.J.; Spidale, N.A.; Wang, B.; Tisch, R. Thymic dendritic cell subsets display distinct efficiencies and mechanisms of intercellular mhc transfer. J. Immunol., 2017, 198(1), 249-256.
Atibalentja, D.F.; Murphy, K.M.; Unanue, E.R. Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol., 2011, 186(3), 1421-1431.
Hadeiba, H.; Lahl, K.; Edalati, A.; Oderup, C.; Habtezion, A.; Pachynski, R.; Nguyen, L.; Ghodsi, A.; Adler, S.; Butcher, E.C. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity, 2012, 36(3), 438-450.
Schlenner, S.M.; Madan, V.; Busch, K.; Tietz, A.; Läufle, C.; Costa, C.; Blum, C.; Fehling, H.J.; Rodewald, H.R. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity, 2010, 32(3), 426-436.
Wu, L.; Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol., 2005, 17(4), 304-312.
Millet, V.; Naquet, P.; Guinamard, R.R. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol., 2008, 38(5), 1257-1263.
Koble, C.; Kyewski, B. The thymic medulla: A unique microenvironment for intercellular self-antigen transfer. J. Exp. Med., 2009, 206(7), 1505-1513.
Nedjic, J.; Aichinger, M.; Emmerich, J.; Mizushima, N.; Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature, 2008, 455(7211), 396-400.
Kloetzel, P.M.; Ossendorp, F. Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr. Opin. Immunol., 2004, 16(1), 76-81.
Nil, A.; Firat, E.; Sobek, V.; Eichmann, K.; Niedermann, G. Expression of housekeeping and immunoproteasome subunit genes is differentially regulated in positively and negatively selecting thymic stroma subsets. Eur. J. Immunol., 2004, 34(10), 2681-2689.
Honey, K.; Rudensky, A.Y. Lysosomal cysteine proteases regulate antigen presentation. Nat. Rev. Immunol., 2003, 3(6), 472-482.
Dong, H.; Chen, J.; Chen, W. Membrane molecules in induction of apoptosis of thymocytes by mouse thymic dendritic cells which express Fas ligands. Sci. China C Life Sci., 1998, 41(2), 189-194.
Cretney, E.; Uldrich, A.P.; McNab, F.W.; Godfrey, D.I.; Smyth, M.J. No requirement for trail in intrathymic negative selection. Int. Immunol., 2008, 20(2), 267-276.
Gascoigne, N.R.; Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol., 2011, 23(2), 207-212.
Leung, M.W.; Shen, S.; Lafaille, J.J. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med., 2009, 206(10), 2121-2130.
Bautista, J.L.; Lio, C.W.; Lathrop, S.K.; Forbush, K.; Liang, Y.; Luo, J.; Rudensky, A.Y.; Hsieh, C.S. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol., 2009, 10(6), 610-617.
Malchow, S.; Leventhal, D.S.; Nishi, S.; Nishi, S.; Fischer, B.I.; Shen, L.; Paner, G.P.; Amit, A.S.; Kang, C.; Geddes, J.E.; Allison, J.P.; Socci, N.D.; Savage, P.A. Aire-dependent thymic development of tumor-associated regulatory T cells. Science, 2013, 339(6124), 1219-1224.
Lee, H.M.; Bautista, J.L.; Scott-Browne, J.; Mohan, J.F.; Hsieh, C.S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity, 2012, 37(3), 475-486.
Wojciech, L.; Ignatowicz, A.; Seweryn, M.; Rempala, G.; Pabla, S.S.; McIndoe, R.A.; Kisielow, P.; Ignatowicz, L. The same self-peptide selects conventional and regulatory CD4+ T cells with identical antigen receptors. Nat. Commun., 2014, 5, 5061.
Hood, J.D.; Zarnitsyna, V.I.; Zhu, C.; Evavold, B.D. Regulatory and t effector cells have overlapping low to high ranges in tcr affinities for self during demyelinating disease. J. Immunol., 2015, 195(9), 4162-4170.
Lio, C.W.; Hsieh, C.S. A two-step process for thymic regulatory T cell development. Immunity, 2008, 28(1), 100-111.
Hinterberger, M.; Wirnsberger, G.; Klein, L. B7/CD28 in central tolerance: Costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Front. Immunol., 2011, 2, 30.
Burchill, M.A.; Yang, J.; Vang, K.B.; Moon, J.J.; Chu, H.H.; Lio, C.W.; Vegoe, A.L.; Hsieh, C.S.; Jenkins, M.K.; Farrar, M.A. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity, 2008, 28(1), 112-121.
Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med., 2003, 198(12), 1875-1886.
Li, M.O.; Sanjabi, S.; Flavell, R.A. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity, 2006, 25(3), 455-471.
Liu, Y.; Zhang, P.; Li, J.; Kulkarni, A.B.; Perruche, S.; Chen, W. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol., 2008, 9(6), 632-640.
Vang, K.B.; Yang, J.; Mahmud, S.A.; Burchill, M.A.; Vegoe, A.L.; Farrar, M.A. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol., 2008, 181(5), 3285-3290.
Burchill, M.A.; Yang, J.; Vogtenhuber, C.; Blazar, B.R.; Farrar, M.A. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol., 2007, 178(1), 280-290.
Tai, X.; Erman, B.; Alag, A.; Mu, J.; Kimura, M.; Katz, G.; Guinter, T.; McCaughtry, T.; Etzensperger, R.; Feigenbaum, L.; Singer, D.S.; Singer, A. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity, 2013, 38(6), 1116-1128.
Tai, X.; Cowan, M.; Feigenbaum, L.; Singer, A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat. Immunol., 2005, 6(2), 152-162.
Weist, B.M.; Kurd, N.; Boussier, J.; Chan, S.W.; Robey, E.A. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol., 2015, 16(6), 635-641.
Lio, C.W.; Dodson, L.F.; Deppong, C.M.; Hsieh, C.S.; Green, J.M. CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J. Immunol., 2010, 184(11), 6007-6013.
Mahmud, S.A.; Manlove, L.S.; Schmitz, H.M.; Xing, Y.; Wang, Y.; Owen, D.L.; Schenkel, J.M.; Boomer, J.S.; Green, J.M.; Yagita, H.; Chi, H.; Hogquist, K.A.; Farrar, M.A. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol., 2014, 15(5), 473-481.
Liu, C.; Wang, H.C.; Yu, S.; Jin, R.; Tang, H.; Liu, Y.F.; Ge, Q.; Sun, X.H.; Zhang, Y. Id1 expression promotes T regulatory cell differentiation by facilitating TCR costimulation. J. Immunol., 2014, 193(2), 663-672.
Williams, J.A.; Zhang, J.; Jeon, H.; Nitta, T.; Ohigashi, I.; Klug, D.; Kruhlak, M.J.; Choudhury, B.; Sharrow, S.O.; Granger, L.; Adams, A.; Eckhaus, M.A.; Jenkinson, S.R.; Richie, E.R.; Gress, R.E.; Takahama, Y.; Hodes, R.J. Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways. J. Immunol., 2014, 192(2), 630-640.
Cuss, S.M.; Green, E.A. Abrogation of CD40-CD154 signaling impedes the homeostasis of thymic resident regulatory T cells by altering the levels of IL-2, but does not affect regulatory T cell development. J. Immunol., 2012, 189(4), 1717-1725.
Lu, F.T.; Yang, W.; Wang, Y.H.; Ma, H.D.; Tang, W.; Yang, J.B.; Li, L.; Ansari, A.A.; Lian, Z.X. Thymic B cells promote thymus-derived regulatory T cell development and proliferation. J. Autoimmun., 2015, 61, 62-72.
Coquet, J.M.; Ribot, J.C.; Bąbała, N.; Middendorp, S.; van der Horst, G.; Xiao, Y.; Neves, J.F.; Fonseca-Pereira, D.; Jacobs, H.; Pennington, D.J.; Silva-Santos, B.; Borst, J. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med., 2013, 210(4), 715-728.
Thiault, N.; Darrigues, J.; Adoue, V.; Gros, M.; Binet, B.; Perals, C.; Leobon, B.; Fazilleau, N.; Joffre, O.P.; Robey, E.A.; van Meerwijk, J.P.; Romagnoli, P. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol., 2015, 16(6), 628-634.
Cebula, A.; Seweryn, M.; Rempala, G.A.; Pabla, S.S.; McIndoe, R.A.; Denning, T.L.; Bry, L.; Kraj, P.; Kisielow, P.; Ignatowicz, L. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature, 2013, 497(7448), 258-262.
Watanabe, N.; Wang, Y.H.; Lee, H.K.; Ito, T.; Wang, Y.H.; Cao, W.; Liu, Y.J. Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature, 2005, 436(7054), 1181-1185.
Hanabuchi, S.; Ito, T.; Park, W.R.; Watanabe, N.; Shaw, J.L.; Roman, E.; Arima, K.; Wang, Y.H.; Voo, K.S.; Cao, W.; Liu, Y.J. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J. Immunol., 2010, 184(6), 2999-3007.
Mazzucchelli, R.; Hixon, J.A.; Spolski, R.; Chen, X.; Li, W.Q.; Hall, V.L.; Willette-Brown, J.; Hurwitz, A.A.; Leonard, W.J.; Durum, S.K. Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood, 2008, 112(8), 3283-3292.
Coquet, J.M.; Ribot, J.C.; Bąbała, N.; Middendorp, S.; van der Horst, G.; Xiao, Y.; Neves, J.F.; Fonseca-Pereira, D.; Jacobs, H.; Pennington, D.J.; Silva-Santos, B.; Borst, J. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med., 2013, 210(4), 715-728.
Shin, J.S.; Ebersold, M.; Pypaert, M.; Delamarre, L.; Hartley, A.; Mellman, I. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature, 2006, 444(7115), 115-118.
Baravalle, G.; Park, H.; McSweeney, M.; Ohmura-Hoshino, M.; Matsuki, Y.; Ishido, S.; Shin, J.S. Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells. J. Immunol., 2011, 187(6), 2966-2973.
De Gassart, A.; Camosseto, V.; Thibodeau, J.; Ceppi, M.; Catalan, N.; Pierre, P.; Gatti, E. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Natl. Acad. Sci. USA, 2008, 105(9), 3491-3496.
Ueno, T.; Hara, K.; Willis, M.S.; Malin, M.A.; Höpken, U.E.; Gray, D.H.; Matsushima, K.; Lipp, M.; Springer, T.A.; Boyd, R.L.; Yoshie, O.; Takahama, Y. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity, 2002, 16(2), 205-218.
Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature, 2004, 427(6792), 355-360.
Zachariah, M.A.; Cyster, J.G. Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science, 2010, 328(5982), 1129-1135.
White, A.J.; Baik, S.; Parnell, S.M.; Holland, A.M.; Brombacher, F.; Jenkinson, W.E.; Anderson, G. A type 2 cytokine axis for thymus emigration. J. Exp. Med., 2017, 214(8), 2205-2216.
Richards, D.M.; Kyewski, B.; Feuerer, M. Re-examining the nature and function of self-reactive t cells. Trends Immunol., 2016, 37(2), 114-125.
Enouz, S.; Carrié, L.; Merkler, D.; Bevan, M.J.; Zehn, D. Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection. J. Exp. Med., 2012, 209(10), 1769-1779.
Wucherpfennig, K.W. T cell receptor crossreactivity as a general property of T cell recognition. Mol. Immunol., 2004, 40(14-15), 1009-1017.
Nelson, R.W.; Beisang, D.; Tubo, N.J.; Dileepan, T.; Wiesner, D.L.; Nielsen, K.; Wüthrich, M.; Klein, B.S.; Kotov, D.I.; Spanier, J.A.; Fife, B.T.; Moon, J.J.; Jenkins, M.K. T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity, 2015, 42(1), 95-107.
Anderson, A.C.; Nicholson, L.B.; Legge, K.L.; Turchin, V.; Zaghouani, H.; Kuchroo, V.K. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: Mechanisms of selection of the self-reactive repertoire. J. Exp. Med., 2000, 191(5), 761-770.
Koehli, S.; Naeher, D.; Galati-Fournier, V.; Zehn, D.; Palmer, E. Optimal T-cell receptor affinity for inducing autoimmunity. Proc. Natl. Acad. Sci. USA, 2014, 111(48), 17248-17253.
Richards, D.M.; Ruggiero, E.; Hofer, A.C.; Sefrin, J.P.; Schmidt, M.; von Kalle, C.; Feuerer, M. The contained self-reactive peripheral t cell repertoire: Size, diversity, and cellular composition. J. Immunol., 2015, 195(5), 2067-2079.
Josefowicz, S.Z.; Lu, L.F.; Rudensky, A.Y. Regulatory T cells: Mechanisms of differentiation and function. Annu. Rev. Immunol., 2012, 30, 531-564.
Ooi, J.D.; Petersen, J.; Tan, Y.H.; Huynh, M.; Willett, Z.J.; Ramarathinam, S.H.; Eggenhuizen, P.J.; Loh, K.L.; Watson, K.A.; Gan, P.Y.; Alikhan, M.A.; Dudek, N.L.; Handel, A.; Hudson, B.G.; Fugger, L.; Power, D.A.; Holt, S.G.; Coates, P.T.; Gregersen, J.W.; Purcell, A.W.; Holdsworth, S.R.; La Gruta, N.L.; Reid, H.H.; Rossjohn, J.; Kitching, A.R. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature, 2017, 545(7653), 243-247.
Jones, A.; Hawiger, D. Peripherally induced regulatory t cells: Recruited protectors of the central nervous system against autoimmune neuroinflammation. Front. Immunol., 2017, 8, 532.
Malhotra, D.; Linehan, J.L.; Dileepan, T.; Lee, Y.J.; Purtha, W.E.; Lu, J.V.; Nelson, R.W.; Fife, B.T.; Orr, H.T.; Anderson, M.S.; Hogquist, K.A.; Jenkins, M.K. Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol., 2016, 17(2), 187-195.
Rocha, B.; von Boehmer, H. Peripheral selection of the T cell repertoire. Science, 1991, 251(4998), 1225-1228.
Hawiger, D.; Inaba, K.; Dorsett, Y.; Guo, M.; Mahnke, K.; Rivera, M.; Ravetch, J.V.; Steinman, R.M.; Nussenzweig, M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med., 2001, 194(6), 769-779.
Hawiger, D.; Masilamani, R.F.; Bettelli, E.; Kuchroo, V.K.; Nussenzweig, M.C. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity, 2004, 20(6), 695-705.
Kretschmer, K.; Apostolou, I.; Hawiger, D.; Khazaie, K.; Nussenzweig, M.C.; von Boehmer, H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol., 2005, 6(12), 1219-1227.
Darrasse-Jèze, G.; Deroubaix, S.; Mouquet, H.; Victora, G.D.; Eisenreich, T.; Yao, K.H.; Masilamani, R.F.; Dustin, M.L.; Rudensky, A.; Liu, K.; Nussenzweig, M.C. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med., 2009, 206(9), 1853-1862.
Welty, N.E.; Staley, C.; Ghilardi, N.; Sadowsky, M.J.; Igyártó, B.Z.; Kaplan, D.H. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J. Exp. Med., 2013, 210(10), 2011-2024.
Josefowicz, S.Z.; Niec, R.E.; Kim, H.Y.; Treuting, P.; Chinen, T.; Zheng, Y.; Umetsu, D.T.; Rudensky, A.Y. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature, 2012, 482(7385), 395-399.
Hasegawa, H.; Matsumoto, T. Mechanisms of tolerance induction by dendritic cells in vivo. Front. Immunol., 2018, 9, 350.
Hawiger, D.; Wan, Y.Y.; Eynon, E.E.; Flavell, R.A. The transcription cofactor Hopx is required for regulatory T cell function in dendritic cell-mediated peripheral T cell unresponsiveness. Nat. Immunol., 2010, 11(10), 962-968.
Sancho, D.; Reis e Sousa, C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu. Rev. Immunol., 2012, 30, 491-529.
Durai, V.; Murphy, K.M. Functions of murine dendritic cells. Immunity, 2016, 45(4), 719-736.
Guilliams, M.; Dutertre, C.A.; Scott, C.L.; McGovern, N.; Sichien, D.; Chakarov, S.; Van Gassen, S.; Chen, J.; Poidinger, M.; De Prijck, S.; Tavernier, S.J.; Low, I.; Irac, S.E.; Mattar, C.N.; Sumatoh, H.R.; Low, G.H.L.; Chung, T.J.K.; Chan, D.K.H.; Tan, K.K.; Hon, T.L.K.; Fossum, E.; Bogen, B.; Choolani, M.; Chan, J.K.Y.; Larbi, A.; Luche, H.; Henri, S.; Saeys, Y.; Newell, E.W.; Lambrecht, B.N.; Malissen, B.; Ginhoux, F. Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species. Immunity, 2016, 45(3), 669-684.
Merad, M.; Sathe, P.; Helft, J.; Miller, J.; Mortha, A. The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol., 2013, 31, 563-604.
Gottschalk, C.; Damuzzo, V.; Gotot, J.; Kroczek, R.A.; Yagita, H.; Murphy, K.M.; Knolle, P.A.; Ludwig-Portugall, I.; Kurts, C. Batf3-dependent dendritic cells in the renal lymph node induce tolerance against circulating antigens. J. Am. Soc. Nephrol., 2013, 24(4), 543-549.
Esterházy, D.; Loschko, J.; London, M.; Jove, V.; Oliveira, T.Y.; Mucida, D. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat. Immunol., 2016, 17(5), 545-555.
Nutsch, K.; Chai, J.N.; Ai, T.L.; Russler-Germain, E.; Feehley, T.; Nagler, C.R.; Hsieh, C.S. Rapid and efficient generation of regulatory t cells to commensal antigens in the periphery. Cell Rep., 2016, 17(1), 206-220.
Muzaki, A.R.; Tetlak, P.; Sheng, J.; Loh, S.C.; Setiagani, Y.A.; Poidinger, M.; Zolezzi, F.; Karjalainen, K.; Ruedl, C. Intestinal CD103(+)CD11b(-) dendritic cells restrain colitis via IFN-γ-induced anti-inflammatory response in epithelial cells. Mucosal Immunol., 2016, 9(2), 336-351.
Iwasaki, A.; Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol., 2015, 16(4), 343-353.
Jones, A.; Bourque, J.; Kuehm, L.; Opejin, A.; Teague, R.M.; Gross, C.; Hawiger, D. Immunomodulatory functions of BTLA and HVEM govern induction of extrathymic regulatory t cells and tolerance by dendritic cells. Immunity, 2016, 45(5), 1066-1077.
Kalekar, L.A.; Schmiel, S.E.; Nandiwada, S.L.; Lam, W.Y.; Barsness, L.O.; Zhang, N.; Stritesky, G.L.; Malhotra, D.; Pauken, K.E.; Linehan, J.L.; O’Sullivan, M.G.; Fife, B.T.; Hogquist, K.A.; Jenkins, M.K.; Mueller, D.L. CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol., 2016, 17(3), 304-314.
Manicassamy, S.; Ravindran, R.; Deng, J.; Oluoch, H.; Denning, T.L.; Kasturi, S.P.; Rosenthal, K.M.; Evavold, B.D.; Pulendran, B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med., 2009, 15(4), 401-409.
Li, M.O.; Flavell, R.A. Contextual regulation of inflammation: A duet by transforming growth factor-beta and interleukin-10. Immunity, 2008, 28(4), 468-476.
Manicassamy, S.; Reizis, B.; Ravindran, R.; Nakaya, H.; Salazar-Gonzalez, R.M.; Wang, Y.C.; Pulendran, B. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science, 2010, 329(5993), 849-853.
Wang, L.; Pino-Lagos, K.; de Vries, V.C.; Guleria, I.; Sayegh, M.H.; Noelle, R.J. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc. Natl. Acad. Sci. USA, 2008, 105(27), 9331-9336.
Wing, K.; Onishi, Y.; Prieto-Martin, P.; Yamaguchi, T.; Miyara, M.; Fehervari, Z.; Nomura, T.; Sakaguchi, S. CTLA-4 control over Foxp3+ regulatory T cell function. Science, 2008, 322(5899), 271-275.
Akbari, O.; Freeman, G.J.; Meyer, E.H.; Greenfield, E.A.; Chang, T.T.; Sharpe, A.H.; Berry, G.; DeKruyff, R.H.; Umetsu, D.T. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat. Med., 2002, 8(9), 1024-1032.
Henderson, J.G.; Opejin, A.; Jones, A.; Gross, C.; Hawiger, D. CD5 instructs extrathymic regulatory T cell development in response to self and tolerizing antigens. Immunity, 2015, 42(3), 471-483.
Kalden, J.R. Emerging Therapies for Rheumatoid Arthritis. Rheumatol. Ther., 2016, 3(1), 31-42.
Miyara, M.; Amoura, Z.; Parizot, C.; Badoual, C.; Dorgham, K. Trad S.; Nochy, D.; Debré, P.; Piette, J.C.; Gorochov, G. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J. Immunol., 2005, 175(12), 8392-8400.
Dwivedi, M.; Kumar, P.; Laddha, N.C.; Kemp, E.H. Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. Autoimmun. Rev., 2016, 15(4), 379-392.
Qiao, Y.C.; Shen, J.; He, L.; Hong, X.Z.; Tian, F.; Pan, Y.H.; Liang, L.; Zhang, X.X.; Zhao, H.L. Changes of regulatory t cells and of proinflammatory and immunosuppressive cytokines in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. J. Diabetes Res., 2016, 20163694957
Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell, 2008, 133(5), 775-787.
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.; Clayberger, C.; Soper, D.M.; Ziegler, S.F.; Bluestone, J.A. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med., 2006, 203(7), 1701-1711.
Salomon, B.; Bluestone, J.A. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol., 2001, 19, 225-252.
Kataoka, H.; Takahashi, S.; Takase, K.; Yamasaki, S.; Yokosuka, T.; Koike, T.; Saito, T. CD25(+)CD4(+) regulatory T cells exert in vitro suppressive activity independent of CTLA-4. Int. Immunol., 2005, 17(4), 421-427.
Bluestone, J.A.; Abbas, A.K. Natural versus adaptive regulatory T cells. Nat. Rev. Immunol., 2003, 3(3), 253-237.
Mucida, D.; Kutchukhidze, N.; Erazo, A.; Russo, M.; Lafaille, J.J.; Curotto de Lafaille, M.A. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest., 2005, 115(7), 1923-1933.
Kingsley, C.I.; Karim, M.; Bushell, A.R.; Wood, K.J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol., 2002, 168(3), 1080-1086.
Fallarino, F.; Grohmann, U.; Hwang, K.W.; Orabona, C.; Vacca, C.; Bianchi, R.; Belladonna, M.L.; Fioretti, M.C.; Alegre, M.L.; Puccetti, P. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol., 2003, 4(12), 1206-1212.
Chen, W.; Jin, W.; Wahl, S.M. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. J. Exp. Med., 1998, 188(10), 1849-1857.
Tagaya, Y.; Bamford, R.N.; DeFilippis, A.P.; Waldmann, T.A. IL-15: A pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity, 1996, 4(4), 329-336.
Dooms, H.; Desmedt, M.; Vancaeneghem, S.; Rottiers, P.; Goossens, V.; Fiers, W.; Grooten, J. Quiescence-inducing and antiapoptotic activities of IL-15 enhance secondary CD4+ T cell responsiveness to antigen. J. Immunol., 1998, 161(5), 2141-2150.
Villablanca, E.J. Retinoic acid-producing DCs and gut-tropic FOXP3+ regulatory T cells in the induction of oral tolerance. OncoImmunology, 2013, 2(2)e22987
Lee, H.M.; Bautista, J.L.; Scott-Browne, J.; Mohan, J.F.; Hsieh, C.S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity, 2012, 37(3), 475-486.
Cebula, A.; Seweryn, M.; Rempala, G.A.; Pabla, S.S.; McIndoe, R.A.; Denning, T.L.; Bry, L.; Kraj, P.; Kisielow, P.; Ignatowicz, L. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature, 2013, 497(7448), 258-262.
Thornton, A.M.; Korty, P.E.; Tran, D.Q.; Wohlfert, E.A.; Murray, P.E.; Belkaid, Y.; Shevach, E.M. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol., 2010, 184(7), 3433-3441.
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.; Yang, Y.; Floess, S.; Huehn, J.; Oh, S.; Li, M.O.; Niec, R.E.; Rudensky, A.Y.; Dustin, M.L.; Littman, D.R.; Lafaille, J.J. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med., 2012, 209(10), 1723-1742.
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.; Ruminski, P.; Weiss, D.; Von Schack, D.; Bluestone, J.A. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med., 2012, 209(10), 1713-1722.
Nutsch, K.; Chai, J.N.; Ai, T.L.; Russler-Germain, E.; Feehley, T.; Nagler, C.R.; Hsieh, C.S. Rapid and efficient generation of regulatory t cells to commensal antigens in the periphery. Cell Rep., 2016, 17(1), 206-220.
Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; Taniguchi, T.; Takeda, K.; Hori, S.; Ivanov, I.I.; Umesaki, Y.; Itoh, K.; Honda, K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science, 2011, 331(6015), 337-341.
Russler-Germain, E.V.; Rengarajan, S.; Hsieh, C.S. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol., 2017, 10(6), 1375-1386.
Atarashi, K.; Tanoue, T.; Oshima, K.; Suda, W.; Nagano, Y.; Nishikawa, H.; Fukuda, S.; Saito, T.; Narushima, S.; Hase, K.; Kim, S.; Fritz, J.V.; Wilmes, P.; Ueha, S.; Matsushima, K.; Ohno, H.; Olle, B.; Sakaguchi, S.; Taniguchi, T.; Morita, H.; Hattori, M.; Honda, K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature, 2013, 500(7461), 232-236.
Mucida, D.; Pino-Lagos, K.; Kim, G.; Nowak, E.; Benson, M.J.; Kronenberg, M.; Noelle, R.J.; Cheroutre, H. Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity, 2009, 30(4), 471-472.
Nolting, J.; Daniel, C.; Reuter, S.; Stuelten, C.; Li, P.; Sucov, H.; Kim, B.G.; Letterio, J.J.; Kretschmer, K.; Kim, H.J.; von Boehmer, H. Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines. J. Exp. Med., 2009, 206(10), 2131-2139.
Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; Takahashi, M.; Fukuda, N.N.; Murakami, S.; Miyauchi, E.; Hino, S.; Atarashi, K.; Onawa, S.; Fujimura, Y.; Lockett, T.; Clarke, J.M.; Topping, D.L.; Tomita, M.; Hori, S.; Ohara, O.; Morita, T.; Koseki, H.; Kikuchi, J.; Honda, K.; Hase, K.; Ohno, H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature, 2013, 504(7480), 446-450.
Arpaia, N.; Campbell, C.; Fan, X.; Dikiy, S.; van der Veeken, J.; deRoos, P.; Liu, H.; Cross, J.R.; Pfeffer, K.; Coffer, P.J.; Rudensky, A.Y. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature, 2013, 504(7480), 451-455.
Chu, H.; Khosravi, A.; Kusumawardhani, I.P.; Kwon, A.H.; Vasconcelos, A.C.; Cunha, L.D.; Mayer, A.E.; Shen, Y.; Wu, W.L.; Kambal, A.; Targan, S.R.; Xavier, R.J.; Ernst, P.B.; Green, D.R.; McGovern, D.P.; Virgin, H.W.; Mazmanian, S.K. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science, 2016, 352(6289), 1116-1120.
Munn, D.H.; Mellor, A.L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol., 2013, 34(3), 137-143.
Zheng, Y.; Josefowicz, S.; Chaudhry, A.; Peng, X.P.; Forbush, K.; Rudensky, A.Y. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature, 2010, 463(7282), 808-812.
Feng, Y.; Arvey, A.; Chinen, T.; van der Veeken, J.; Gasteiger, G.; Rudensky, A.Y. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell, 2014, 158(4), 749-763.
Koch, M.A.; Tucker-Heard, G.; Perdue, N.R.; Killebrew, J.R.; Urdahl, K.B.; Campbell, D.J. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol., 2009, 10(6), 595-602.
Kitagawa, Y.; Sakaguchi, S. Molecular control of regulatory T cell development and function. Curr. Opin. Immunol., 2017, 49, 64-70.
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.; Frucht, D.M.; Dumitriu, B.; Scheinberg, P.; Folio, L.R.; Frein, C.A.; Price, S.; Koh, C.; Heller, T.; Seroogy, C.M.; Huttenlocher, A.; Rao, V.K.; Su, H.C.; Kleiner, D.; Notarangelo, L.D.; Rampertaap, Y.; Olivier, K.N.; McElwee, J.; Hughes, J.; Pittaluga, S.; Oliveira, J.B.; Meffre, E.; Fleisher, T.A.; Holland, S.M.; Lenardo, M.J.; Tangye, S.G.; Uzel, G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science, 2014, 345(6204), 1623-1627.
Schubert, D.; Bode, C.; Kenefeck, R.; Hou, T.Z.; Wing, J.B.; Kennedy, A.; Bulashevska, A.; Petersen, B.S.; Schäffer, A.A.; Grüning, B.A.; Unger, S.; Frede, N.; Baumann, U.; Witte, T.; Schmidt, R.E.; Dueckers, G.; Niehues, T.; Seneviratne, S.; Kanariou, M.; Speckmann, C.; Ehl, S.; Rensing-Ehl, A.; Warnatz, K.; Rakhmanov, M.; Thimme, R.; Hasselblatt, P.; Emmerich, F.; Cathomen, T.; Backofen, R.; Fisch, P.; Seidl, M.; May, A.; Schmitt-Graeff, A.; Ikemizu, S.; Salzer, U.; Franke, A.; Sakaguchi, S.; Walker, L.S.K.; Sansom, D.M.; Grimbacher, B. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med., 2014, 20(12), 1410-1416.
Lo, B.; Zhang, K.; Lu, W.; Zheng, L.; Zhang, Q.; Kanellopoulou, C.; Zhang, Y.; Liu, Z.; Fritz, J.M.; Marsh, R.; Husami, A.; Kissell, D.; Nortman, S.; Chaturvedi, V.; Haines, H.; Young, L.R.; Mo, J.; Filipovich, A.H.; Bleesing, J.J.; Mustillo, P.; Stephens, M.; Rueda, C.M.; Chougnet, C.A.; Hoebe, K.; McElwee, J.; Hughes, J.D.; Karakoc-Aydiner, E.; Matthews, H.F.; Price, S.; Su, H.C.; Rao, V.K.; Lenardo, M.J.; Jordan, M.B. Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science, 2015, 349(4246), 436-440.
Kitagawa, Y.; Ohkura, N.; Kidani, Y.; Vandenbon, A.; Hirota, K.; Kawakami, R.; Yasuda, K.; Motooka, D.; Nakamura, S.; Kondo, M.; Taniuchi, I.; Kohwi-Shigematsu, T.; Sakaguchi, S. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol., 2017, 18(2), 173-183.
Vahedi, G.; Kanno, Y.; Furumoto, Y.; Jiang, K.; Parker, S.C.; Erdos, M.R.; Davis, S.R.; Roychoudhuri, R.; Restifo, N.P.; Gadina, M.; Tang, Z.; Ruan, Y.; Collins, F.S.; Sartorelli, V.; O’Shea, J.J. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature, 2015, 520(7548), 558-562.
Mascanfroni, I.D.; Takenaka, M.C.; Yeste, A.; Patel, B.; Wu, Y.; Kenison, J.E.; Siddiqui, S.; Basso, A.S.; Otterbein, L.E.; Pardoll, D.M.; Pan, F.; Priel, A.; Clish, C.B.; Robson, S.C.; Quintana, F.J. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat. Med., 2015, 21(6), 638-646.
Newton, R.; Priyadharshini, B.; Turka, L.A. Immunometabolism of regulatory T cells. Nat. Immunol., 2016, 17(6), 618-625.
Gregori, S.; Roncarolo, M.G. Engineered T regulatory type 1 cells for clinical application. Front. Immunol., 2018, 9, 233.
Roncarolo, M.G.; Gregori, S.; Bacchetta, R.; Battaglia, M. Tr1 cells and the counter-regulation of immunity: Natural mechanisms and therapeutic applications. Curr. Top. Microbiol. Immunol., 2014, 380, 39-68.
Bacchetta, R.; Lucarelli, B.; Sartirana, C.; Gregori, S.; Lupo Stanghellini, M.T.; Miqueu, P.; Tomiuk, S.; Hernandez-Fuentes, M.; Gianolini, M.E.; Greco, R.; Bernardi, M.; Zappone, E.; Rossini, S.; Janssen, U.; Ambrosi, A.; Salomoni, M.; Peccatori, J.; Ciceri, F.; Roncarolo, M.G. Immunological outcome in haploidentical-hsc transplanted patients treated with IL-10-anergized donor t cells. Front. Immunol., 2014, 5, 16.
Desreumaux, P.; Foussat, A.; Allez, M.; Beaugerie, L.; Hébuterne, X.; Bouhnik, Y.; Nachury, M.; Brun, V.; Bastian, H.; Belmonte, N.; Ticchioni, M.; Duchange, A.; Morel-Mandrino, P.; Neveu, V.; Clerget-Chossat, N.; Forte, M.; Colombel, J.F. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology., , 2012, 143(5), 1207-1217. e1-2.
Andolfi, G.; Fousteri, G.; Rossetti, M.; Magnani, C.F.; Jofra, T.; Locafaro, G.; Bondanza, A.; Gregori, S.; Roncarolo, M.G. Enforced IL-10 expression confers type 1 regulatory T cell (Tr1) phenotype and function to human CD4(+) T cells. Mol. Ther., 2012, 20(9), 1778-1790.
Locafaro, G.; Andolfi, G.; Russo, F.; Cesana, L.; Spinelli, A.; Camisa, B.; Ciceri, F.; Lombardo, A.; Bondanza, A.; Roncarolo, M.G.; Gregori, S. IL-10-engineered human CD4+ Tr1 cells eliminate myeloid leukemia in an hla class I-dependent mechanism. Mol. Ther., 2017, 25(10), 2254-2269.
Mora, J.R.; Iwata, M.; von Andrian, U.H. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat. Rev. Immunol., 2008, 8(9), 685-698.
Benson, M.J.; Pino-Lagos, K.; Rosemblatt, M.; Noelle, R.J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med., 2007, 204(8), 1765-1774.
Provvedini, D.M.; Tsoukas, C.D.; Deftos, L.J.; Manolagas, S.C. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science, 1983, 221(4616), 1181-1183.
Jeffery, L.E.; Burke, F.; Mura, M.; Zheng, Y.; Qureshi, O.S.; Hewison, M.; Walker, L.S.; Lammas, D.A.; Raza, K.; Sansom, D.M. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol., 2009, 183(9), 5458-5467.
Barrat, F.J.; Cua, D.J.; Boonstra, A.; Richards, D.F.; Crain, C.; Savelkoul, H.F.; de Waal-Malefyt, R.; Coffman, R.L.; Hawrylowicz, C.M.; O’Garra, A. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med., 2002, 195(5), 603-616.
Nikolouli, E.; Hardtke-Wolenski, M.; Hapke, M.; Beckstette, M.; Geffers, R.; Floess, S.; Jaeckel, E.; Huehn, J. Alloantigen-induced regulatory t cells generated in presence of vitamin c display enhanced stability of foxp3 expression and promote skin allograft acceptance. Front. Immunol., 2017, 8, 748.
Oyarce, K.; Campos-Mora, M. Gajardo-Carrasco, T.; Pino-Lagos, K. Vitamin c fosters the in vivo differentiation of peripheral CD4+ Foxp3- t cells into CD4+ Foxp3+ regulatory t cells but impairs their ability to prolong skin allograft survival. Front. Immunol., 2018, 9, 112.
Kaulmann, A.; Bohn, T. Carotenoids, inflammation, and oxidative stress--implications of cellular signaling pathways and relation to chronic disease prevention. Nutr. Res., 2014, 34(11), 907-929.
McEneny, J.; Wade, L.; Young, I.S.; Masson, L.; Duthie, G.; McGinty, A.; McMaster, C.; Thies, F. Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals. J. Nutr. Biochem., 2013, 24(1), 163-168.
Xu, X.R.; Zou, Z.Y.; Xiao, X.; Huang, Y.M.; Wang, X.; Lin, X.M. Effects of lutein supplement on serum inflammatory cytokines, ApoE and lipid profiles in early atherosclerosis population. J. Atheroscler. Thromb., 2013, 20(2), 170-177.
Jørgensen, S.P.; Agnholt, J.; Glerup, H.; Lyhne, S.; Villadsen, G.E.; Hvas, C.L.; Bartels, L.E.; Kelsen, J.; Christensen, L.A.; Dahlerup, J.F. Clinical trial: Vitamin D3 treatment in Crohn’s disease - A randomized double-blind placebo-controlled study. Aliment. Pharmacol. Ther., 2010, 32(3), 377-383.
Yang, L.; Weaver, V.; Smith, J.P.; Bingaman, S.; Hartman, T.J.; Cantorna, M.T. Therapeutic effect of vitamin d supplementation in a pilot study of Crohn’s patients. Clin. Transl. Gastroenterol., 2013, 4e33
Xia, J.; Shi, L.; Zhao, L.; Xu, F. Impact of vitamin D supplementation on the outcome of tuberculosis treatment: A systematic review and meta-analysis of randomized controlled trials. Chin. Med. J. (Engl.), 2014, 127(17), 3127-3134.
Burton, J.M.; Kimball, S.; Vieth, R.; Bar-Or, A.; Dosch, H.M.; Cheung, R.; Gagne, D.; D’Souza, C.; Ursell, M.; O’Connor, P. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology, 2010, 74(23), 1852-1859.
Soilu-Hänninen, M.; Aivo, J.; Lindström, B.M.; Elovaara, I.; Sumelahti, M.L.; Färkkilä, M.; Tienari, P.; Atula, S.; Sarasoja, T.; Herrala, L.; Keskinarkaus, I.; Kruger, J.; Kallio, T.; Rocca, M.A.; Filippi, M. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatry, 2012, 83(5), 565-571.
Derakhshandi, H.; Etemadifar, M.; Feizi, A.; Abtahi, S.H.; Minagar, A.; Abtahi, M.A.; Abtahi, Z.A.; Dehghani, A.; Sajjadi, S.; Tabrizi, N. Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial. Acta Neurol. Belg., 2013, 113(3), 257-263.
Mosayebi, G.; Ghazavi, A.; Ghasami, K.; Jand, Y.; Kokhaei, P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol. Invest., 2011, 40(6), 627-639.
Kampman, M.T.; Steffensen, L.H.; Mellgren, S.I.; Jørgensen, L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult. Scler., 2012, 18(8), 1144-1151.
Osganian, S.K.; Stampfer, M.J.; Rimm, E.; Spiegelman, D.; Hu, F.B.; Manson, J.E.; Willett, W.C. Vitamin C and risk of coronary heart disease in women. J. Am. Coll. Cardiol., 2003, 42(2), 246-252.
Knekt, P.; Reunanen, A.; Järvinen, R.; Seppänen, R.; Heliövaara, M.; Aromaa, A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am. J. Epidemiol., 1994, 139(12), 1180-1189.
Rimm, E.B.; Stampfer, M.J.; Ascherio, A.; Giovannucci, E.; Colditz, G.A.; Willett, W.C. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med., 1993, 328(20), 1450-1456.
Enstrom, J.E.; Kanim, L.E.; Klein, M.A. Vitamin C intake and mortality among a sample of the United States population. Epidemiology, 1992, 3(3), 194-202.
Ness, A.; Egger, M.; Smith, G.D. Role of antioxidant vitamins in prevention of cardiovascular diseases. Meta-analysis seems to exclude benefit of vitamin C supplementation. BMJ, 1999, 319(7209), 577.
Sabharwal, A.K.; May, J.M. alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. Mol. Cell. Biochem., 2008, 309(1-2), 125-132.
Hoffman, R.P.; Dye, A.S.; Bauer, J.A. Ascorbic acid blocks hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes. Pediatr. Diabetes, 2012, 13(8), 607-610.
Chambial, S.; Dwivedi, S.; Shukla, K.K.; John, P.J.; Sharma, P. Vitamin C in disease prevention and cure: An overview. Indian J. Clin. Biochem., 2013, 28(4), 314-328.
Luerce, T.D.; Gomes-Santos, A.C.; Rocha, C.S.; Moreira, T.G.; Cruz, D.N.; Lemos, L.; Sousa, A.L.; Pereira, V.B.; de Azevedo, M.; Moraes, K.; Cara, D.C.; LeBlanc, J.G.; Azevedo, V.; Faria, A.M.C.; Miyoshi, A. Anti-inflammatory effects of Lactococcus lactis NCDO 2118 during the remission period of chemically induced colitis. Gut Pathog., 2014, 6, 33.
Maruo, T.; Gotoh, Y.; Nishimura, H.; Ohashi, S.; Toda, T.; Takahashi, K. Oral administration of milk fermented with Lactococcus lactis subsp. Cremoris FC protects mice against influenza virus infection. Lett. Appl. Microbiol., 2012, 55(2), 135-140.
Braat, H.; Rottiers, P.; Hommes, D.W.; Huyghebaert, N.; Remaut, E.; Remon, J.P.; van Deventer, S.J.; Neirynck, S.; Peppelenbosch, M.P.; Steidler, L. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol., 2006, 4(6), 754-759.
Vermeire, S.; Van Assche, G.; Rutgeerts, P. Postinfectious irritable bowel syndrome: A genetic link identified? Gastroenterology, 2010, 138(4), 1246-1249.
Martín, R.; Chain, F.; Miquel, S.; Natividad, J.M.; Sokol, H.; Verdu, E.F.; Langella, P.; Bermúdez-Humarán, L.G. Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation. Hum. Vaccin. Immunother., 2014, 10(6), 1611-1621.
Cook, D.P.; Gysemans, C.; Mathieu, C. Lactococcus lactis as a versatile vehicle for tolerogenic Immunotherapy. Front. Immunol., 2018, 8, 1961.
Polyphenols in human health and disease.In; Watson RR, Preedy V, Zibaldi S. Eds. Elsevier, 2014, Vol. 1, pp. 1-912. ISBN: 978-0-12- 398472-2.
Polyphenols in human health and disease.In; Watson RR, Preedy V, Zibaldi S. Eds. Elsevier , 2014, Vol. 2, pp. 1-592. ISBN: 978-0-12- 398472-2.
Marzulli, G.; Magrone, T.; Kawaguchi, K.; Kumazawa, Y.; Jirillo, E. Fermented grape marc (FGM): Immunomodulating properties and its potential exploitation in the treatment of neurodegenerative diseases. Curr. Pharm. Des., 2012, 18(1), 43-50.
Kawaguchi, K.; Matsumoto, T.; Kumazawa, Y. Effects of antioxidant polyphenols on TNF-alpha-related diseases. Curr. Top. Med. Chem., 2011, 11(14), 1767-1779.
Magrone, T.; Jirillo, E.; Spagnoletta, A.; Magrone, M.; Russo, M.A.; Fontana, S.; Laforgia, F.; Donvito, I.; Campanella, A.; Silvestris, F.; De Pergola, G. Immune profile of obese people and in vitro effects of red grape polyphenols on peripheral blood mononuclear cells. Oxid. Med. Cell. Longev., 2017, 20179210862
Vitale, E.; Jirillo, E.; Magrone, T. Determination of body mass index and physical activity in normal weight children and evaluation of salivary levels of IL-10 and IL-17. Clin. Immunol. Endocr. Metab. Drugs, 2014, 1(2), 81-88.
Casas, R.; Sacanella, E.; Estruch, R. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases. Endocr. Metab. Immune Disord. Drug Targets, 2014, 14(4), 245-254.
Miglio, C.; Peluso, I.; Raguzzini, A.; Villaño, D.V.; Cesqui, E.; Catasta, G.; Toti, E.; Serafini, M. Fruit juice drinks prevent endogenous antioxidant response to high-fat meal ingestion. Br. J. Nutr., 2014, 111(2), 294-300.
LaMothe, R.A.; Kolte, P.N.; Vo, T.; Ferrari, J.D.; Gelsinger, T.C.; Wong, J.; Chan, V.T.; Ahmed, S.; Srinivasan, A.; Deitemeyer, P.; Maldonado, R.A.; Kishimoto, T.K. Tolerogenic nanoparticles induce antigen-specific regulatory T cells and provide therapeutic efficacy and transferrable tolerance against experimental autoimmune encephalomyelitis. Front. Immunol., 2018, 9, 281.
Kishimoto, T.K.; Ferrari, J.D.; LaMothe, R.A.; Kolte, P.N.; Griset, A.P.; O’Neil, C.; Chan, V.; Browning, E.; Chalishazar, A.; Kuhlman, W.; Fu, F.N.; Viseux, N.; Altreuter, D.H.; Johnston, L.; Maldonado, R.A. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat. Nanotechnol., 2016, 11(10), 890-899.
Lim, H.H.; Yi, H.; Kishimoto, T.K.; Gao, F.; Sun, B.; Kishnani, P.S. A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease. Mol. Genet. Metab. Rep., 2017, 13, 18-22.
Zhang, A.H.; Rossi, R.J.; Yoon, J.; Wang, H.; Scott, D.W. Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation. Cell. Immunol., 2016, 301, 74-81.
Sands, E.; Kivitz, A.; Johnston, L.; Kishimoto, T.K. THUO4 22 sel. 212. Enhanced serum uric acid control in hyperucemic patients through selective mitigation of anti-drug antibodies against Pegsitilase. Ann. Rhem. Dis., 2017, 76, 367.
Picelli, S.; Björklund, Å.K.; Faridani, O.R.; Sagasser, S.; Winberg, G.; Sandberg, R. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods, 2013, 10(11), 1096-1098.
Shalek, A.K.; Satija, R.; Shuga, J.; Trombetta, J.J.; Gennert, D.; Lu, D.; Chen, P.; Gertner, R.S.; Gaublomme, J.T.; Yosef, N.; Schwartz, S.; Fowler, B.; Weaver, S.; Wang, J.; Wang, X.; Ding, R.; Raychowdhury, R.; Friedman, N.; Hacohen, N.; Park, H.; May, A.P.; Regev, A. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature, 2014, 510(7505), 363-369.
Jaitin, D.A.; Weiner, A.; Yofe, I.; Lara-Astiaso, D.; Keren-Shaul, H.; David, E.; Salame, T.M.; Tanay, A.; van Oudenaarden, A.; Amit, I. Dissecting immune circuits by linking CRISPR-pooled screens with single-cell RNA-seq. Cell, 2016, 167(7), 1883-1896.e15.
Vendelova, E.; Ashour, D.; Blank, P.; Erhard, F.; Saliba, A.E.; Kalinke, U.; Lutz, M.B. Tolerogenic transcriptional signatures of steady-state and pathogen-induced dendritic cells. Front. Immunol., 2018, 9, 333.

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Year: 2019
Page: [580 - 593]
Pages: 14
DOI: 10.2174/1871530319666181211161721
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