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Dissecting Emerging Aspects of Regulatory Circuitry in Man and Mice: Regulatory T Cell Biology

DOI: 10.4236/abb.2018.99031, PP. 443-468

Keywords: Regulatory T Cells, Foxp3, tTreg, pTreg, IL-10, TGF-β, Helios, Neuropilin-1

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Abstract:

Regulatory T cells (Treg), a component of adaptive immunity, are well known for their immunosuppressive roles and their ability to maintain the balance between the immunological and pathological reactions. Treg have been shown to provide protective responses and their depletion has resulted severe pathology in some pathogen infections. The work presented here has unravelled the potential of regulatory cells in the immune system including different repertoir of Treg cell subsets, markers to distinguish them, Treg suppression mechanisms in the pathogenesis of various infections and summarize different mouse models depleting Tregs. These findings would help set up future avenues of research to elucidate a key mechanism of action of these cells and provide new therapeutic insights for pathogenesis and also for broader antibacterial/antiviral/antiproliferative immunity.

 References

[1]  Belkaid, Y. (2007) Regulatory T Cells and Infection: A Dangerous Necessity. Nature Reviews Immunology, 7, 875-888.
https://doi.org/10.1038/nri2189
[2]  Povoleri, G.A., et al. (2013) Thymic versus Induced Regulatory T Cells—Who Regulates the Regulators? Frontiers in Immunology, 4, 169.
https://doi.org/10.3389/fimmu.2013.00169
[3]  Liston, A. and Gray, D.H. (2014) Homeostatic Control of Regulatory T Cell Diversity. Nature Reviews Immunology, 14, 154-165.
https://doi.org/10.1038/nri3605
[4]  Maizels, R.M. and Smith, K.A. (2011) Regulatory T Cells in Infection. Advances in Immunology, 112, 73-136.
https://doi.org/10.1016/B978-0-12-387827-4.00003-6
[5]  Mittrucker, H.W. and Kaufmann, S.H. (2004) Mini-Review: Regulatory T Cells and Infection: Suppression Revisited. European Journal of Immunology, 34, 306-312.
https://doi.org/10.1002/eji.200324578
[6]  Sakaguchi, S., et al. (2001) Immunologic Tolerance Maintained by CD25+ CD4+ Regulatory T Cells: Their Common Role in Controlling Autoimmunity, Tumor Immunity, and Transplantation Tolerance. Immunological Reviews, 182, 18-32.
https://doi.org/10.1034/j.1600-065X.2001.1820102.x
[7]  Belkaid, Y. and Rouse, B.T. (2005) Natural Regulatory T Cells in Infectious Disease. Nature Immunology, 6, 353-360.
https://doi.org/10.1038/ni1181
[8]  Umetsu, D.T. and De Kruyff, R.H. (2006) The Regulation of Allergy and Asthma. Immunological Reviews, 212, 238-255.
https://doi.org/10.1111/j.0105-2896.2006.00413.x
[9]  Fehervari, Z. and Sakaguchi, S. (2004) CD4+ Tregs and Immune Control. Journal of Clinical Investigation, 114, 1209-1217.
https://doi.org/10.1172/JCI200423395
[10]  Baecher-Allan, C., et al. (2003) CD4+CD25+ Regulatory Cells from Human Peripheral Blood Express Very High Levels of CD25 ex Vivo. Novartis Foundation Symposium, 252, 67-91, 106-114.
[11]  Baecher-Allan, C., et al. (2001) CD4+CD25 High Regulatory Cells in Human Peripheral Blood. The Journal of Immunology, 167, 1245-1253.
https://doi.org/10.4049/jimmunol.167.3.1245
[12]  Itoh, M., et al. (1999) Thymus and Autoimmunity: Production of CD25+CD4+ Naturally Anergic and Suppressive T Cells as a Key Function of the Thymus in Maintaining Immunologic Self-Tolerance. The Journal of Immunology, 162, 5317-5326.
[13]  Yi, H., et al. (2006) The Phenotypic Characterization of Naturally Occurring Regulatory CD4+CD25+ T Cells. Cellular & Molecular Immunology, 3, 189-195.
[14]  Deaglio, S., et al. (2007) Adenosine Generation Catalyzed by CD39 and CD73 Expressed on Regulatory T Cells Mediates Immune Suppression. The Journal of Experimental Medicine, 204, 1257-1265.
https://doi.org/10.1084/jem.20062512
[15]  Fontenot, J.D. and Rudensky, A.Y. (2004) Molecular Aspects of Regulatory T Cell Development. Seminars in Immunology, 16, 73-80.
https://doi.org/10.1016/j.smim.2003.12.002
[16]  Ustun, C., Miller, J.S., Munn, D.H., Weisdorf, D.J. and Blazar, B.R. (2011) Regulatory T Cells in Acute Myelogenous Leukemia: Is It Time for Immunomodulation? Blood, 118, 5084-5095.
https://doi.org/10.1182/blood-2011-07-365817
[17]  Piccirillo, C.A. and Shevach, E.M. (2004) Naturally-Occurring CD4+ CD25+ Immunoregulatory T Cells: Central Players in the Arena of Peripheral Tolerance. Seminars in Immunology, 16, 81-88.
https://doi.org/10.1016/j.smim.2003.12.003
[18]  Leithauser, F., Meinhardt-Krajina, T., Fink, K., Wotschke, B., Moller, P. and Reimann, J. (2006) Foxp3-Expressing CD103+ Regulatory T Cells Accumulate in Dendritic Cell Aggregates of the Colonic Mucosa in Murine Transfer Colitis. American Journal of Pathology, 168, 1898-1909.
https://doi.org/10.2353/ajpath.2006.050228
[19]  Needham, D.J., Lee, J.X. and Beilharz, M.W. (2006) Intra-Tumoural Regulatory T Cells: A Potential New Target in Cancer Immunotherapy. Biochemical and Biophysical Research Communications, 343, 684-691.
https://doi.org/10.1016/j.bbrc.2006.03.018
[20]  Sakaguchi, S. (2005) Naturally Arising Foxp3-Expressing CD25+ CD4+ Regulatory T Cells in Immunological Tolerance to Self and Non-Self. Nature Immunology, 6, 345-352.
https://doi.org/10.1038/ni1178
[21]  Buckner, J.H. (2010) Mechanisms of Impaired Regulation by CD4(+) CD25(+) FOXP3(+) Regulatory T Cells in Human Autoimmune Diseases. Nature Reviews Immunology, 10, 849-859.
https://doi.org/10.1038/nri2889
[22]  Fontenot, J.D. and Rudensky, A.Y. (2005) A Well Adapted Regulatory Contrivance: Regulatory T Cell Development and the Forkhead Family Transcription Factor Foxp3. Nature Immunology, 6, 331-337.
https://doi.org/10.1038/ni1179
[23]  Brunkow, M.E., et al. (2001) Disruption of a New Forkhead/Winged-Helix Protein, Scurfin, Results in the Fatal Lymphoproliferative Disorder of the Scurfy Mouse. Nature Genetics, 27, 68-73.
https://doi.org/10.1038/83784
[24]  Fontenot, J.D., Gavin, M.A. and Rudensky, A.Y. (2003) Foxp3 Programs the Development and Function of CD4+ CD25+ Regulatory T Cells. Nature Immunology, 4, 330-336.
https://doi.org/10.1038/ni904
[25]  Hori, S., Nomura, T. and Sakaguchi, S. (2003) Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science, 299, 1057-1061.
https://doi.org/10.1126/science.1079490
[26]  Fontenot, J.D., Rasmussen, J.P., Williams, L.M., Dooley, J.L., Farr, A.G. and Rudensky, A.Y. (2005) Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3. Immunity, 22, 329-341.
https://doi.org/10.1016/j.immuni.2005.01.016
[27]  Bennett, C.L., et al. (2001) The Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX) Is Caused by Mutations of FOXP3. Nature Genetics, 27, 20-21.
https://doi.org/10.1038/83713
[28]  Wildin, R.S., et al. (2001) X-Linked Neonatal Diabetes Mellitus, Enteropathy and Endocrinopathy Syndrome Is the Human Equivalent of Mouse Scurfy. Nature Genetics, 27, 18-20.
https://doi.org/10.1038/83707
[29]  Khattri, R., Cox, T., Yasayko, S.A. and Ramsdell, F. (2003) An Essential Role for Scurfin in CD4+ CD25+ T Regulatory Cells. Nature Immunology, 4, 337-342.
https://doi.org/10.1038/ni909
[30]  Lu, L.F. and Rudensky, A. (2009) Molecular Orchestration of Differentiation and Function of Regulatory T Cells. Genes & Development, 23, 1270-1282.
https://doi.org/10.1101/gad.1791009
[31]  Wan, Y.Y. and Flavell, R.A. (2005) Identifying Foxp3-Expressing Suppressor T Cells with a Bicistronic Reporter. Proceedings of the National Academy of Sciences, 102, 5126-5131.
https://doi.org/10.1073/pnas.0501701102
[32]  Williams, L.M. and Rudensky, A.Y. (2007) Maintenance of the Foxp3-Dependent Developmental Program in Mature Regulatory T Cells Requires Continued Expression of Foxp3. Nature Immunology, 8, 277-284.
https://doi.org/10.1038/ni1437
[33]  Rudensky, A.Y. (2011) Regulatory T Cells and Foxp3. Immunological Reviews, 241, 260-268.
https://doi.org/10.1111/j.1600-065X.2011.01018.x
[34]  Seroogy, C.M. and Gern, J.E. (2005) The Role of T Regulatory Cells in Asthma. Journal of Allergy and Clinical Immunology, 116, 996-999.
https://doi.org/10.1016/j.jaci.2005.07.015
[35]  Nishikawa, H. and Sakaguchi, S. (2010) Regulatory T Cells in Tumor Immunity. International Journal of Cancer, 127, 759-767.
https://doi.org/10.1002/ijc.25429
[36]  Arpaia, N., et al. (2013) Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation. Nature, 504, 451-455.
https://doi.org/10.1038/nature12726
[37]  Aandahl, E.M., Michaelsson, J., Moretto, W.J., Hecht, F.M. and Nixon, D.F. (2004) Human CD4+ CD25+ Regulatory T Cells Control T-Cell Responses to Human Immunodeficiency Virus and Cytomegalovirus Antigens. Journal of Virology, 78, 2454-2459.
https://doi.org/10.1128/JVI.78.5.2454-2459.2004
[38]  McNally, A., Hill, G.R., Sparwasser, T., Thomas, R. and Steptoe, R.J. (2011) CD4+ CD25+ Regulatory T Cells Control CD8+ T-Cell Effector Differentiation by Modulating IL-2 Homeostasis. Proceedings of the National Academy of Sciences, 108, 7529-7534.
https://doi.org/10.1073/pnas.1103782108
[39]  Terme, M., Chaput, N., Combadiere, B., Ma, A., Ohteki, T. and Zitvogel, L. (2008) Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells. The Journal of Immunology, 180, 4679-4686.
https://doi.org/10.4049/jimmunol.180.7.4679
[40]  Iikuni, N., Lourenco, E.V., Hahn, B.H. and La Cava, A. (2009) Cutting Edge: Regulatory T Cells Directly Suppress B Cells in Systemic Lupus Erythematosus. The Journal of Immunology, 183, 1518-1522.
https://doi.org/10.4049/jimmunol.0901163
[41]  Chaudhry, A., et al. (2009) CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner. Science, 326, 986-991.
https://doi.org/10.1126/science.1172702
[42]  Ghiringhelli, F., Ménard, C., Martin, F. and Zitvogel, L. (2006) The Role of Regulatory T Cells in the Control of Natural Killer Cells: Relevance during Tumor Progression. Immunological Reviews, 214, 229-238.
https://doi.org/10.1111/j.1600-065X.2006.00445.x
[43]  Taams, L.S., et al. (2005) Modulation of Monocyte/Macrophage Function by Human CD4+ CD25+ Regulatory T Cells. Human Immunology, 66, 222-230.
https://doi.org/10.1016/j.humimm.2004.12.006
[44]  Gri, G., et al. (2008) CD4+ CD25+ Regulatory T Cells Suppress Mast Cell Degranulation and Allergic Responses through OX40-OX40L Interaction. Immunity, 29, 771-781.
https://doi.org/10.1016/j.immuni.2008.08.018
[45]  Jonuleit, H. and Schmitt, E. (2003) The Regulatory T Cell Family: Distinct Subsets and Their Interrelations. The Journal of Immunology, 171, 6323-6327.
https://doi.org/10.4049/jimmunol.171.12.6323
[46]  Curotto de Lafaille, M.A. and Lafaille, J.J. (2009) Natural and Adaptive Foxp3+ Regulatory T Cells: More of the Same or a Division of Labor? Immunity, 30, 626-635.
https://doi.org/10.1016/j.immuni.2009.05.002
[47]  Abbas, A.K., et al. (2013) Regulatory T Cells: Recommendations to Simplify the Nomenclature. Nature Immunology, 14, 307-308.
https://doi.org/10.1038/ni.2554
[48]  Shevach, E.M. and Thornton, A.M. (2014) tTregs, pTregs, and iTregs: Similarities and Differences. Immunological Reviews, 259, 88-102.
https://doi.org/10.1111/imr.12160
[49]  Bayer, A.L., Yu, A., Adeegbe, D. and Malek, T.R. (2005) Essential Role for Interleukin-2 for CD4(+) CD25(+) T Regulatory Cell Development during the Neonatal Period. The Journal of Experimental Medicine, 201, 769-777.
https://doi.org/10.1084/jem.20041179
[50]  Lim, H.W., Broxmeyer, H.E. and Kim, C.H. (2006) Regulation of Trafficking Receptor Expression in Human Forkhead Box P3+ Regulatory T Cells. The Journal of Immunology, 177, 840-851.
https://doi.org/10.4049/jimmunol.177.2.840
[51]  Shevach, E.M. (2009) Mechanisms of Foxp3+ T Regulatory Cell-Mediated Suppression. Immunity, 30, 636-645.
https://doi.org/10.1016/j.immuni.2009.04.010
[52]  Rubtsov, Y.P., et al. (2010) Stability of the Regulatory T Cell Lineage in Vivo. Science, 329, 1667-1671.
https://doi.org/10.1126/science.1191996
[53]  Engel, M., Sidwell, T., Vasanthakumar, A., Grigoriadis, G. and Banerjee, A. (2013) Thymic Regulatory T Cell Development: Role of Signalling Pathways and Transcription Factors. Clinical & Developmental Immunology, 2013, Article ID: 617595.
https://doi.org/10.1155/2013/617595
[54]  Caramalho, I., Nunes-Cabaco, H., Foxall, R.B. and Sousa, A.E. (2015) Regulatory T-Cell Development in the Human Thymus. Frontiers in Immunology, 6, 395.
https://doi.org/10.3389/fimmu.2015.00395
[55]  Beissert, S., Schwarz, A. and Schwarz, T. (2006) Regulatory T Cells. Journal of Investigative Dermatology, 126, 15-24.
https://doi.org/10.1038/sj.jid.5700004
[56]  Jordan, M.S., et al. (2001) Thymic Selection of CD4+ CD25+ Regulatory T Cells Induced by an Agonist Self-Peptide. Nature Immunology, 2, 301-306.
https://doi.org/10.1038/86302
[57]  Horwitz, D.A., Zheng, S.G. and Gray, J.D. (2008) Natural and TGF-Beta-Induced Foxp3(+) CD4(+) CD25(+) Regulatory T Cells Are Not Mirror Images of Each Other. Trends in Immunology, 29, 429-435.
https://doi.org/10.1016/j.it.2008.06.005
[58]  Salomon, B., et al. (2000) B7/CD28 Costimulation Is Essential for the Homeostasis of the CD4+ CD25+ Immunoregulatory T Cells That Control Autoimmune Diabetes. Immunity, 12, 431-440.
https://doi.org/10.1016/S1074-7613(00)80195-8
[59]  Vang, K.B., et al. (2010) Cutting Edge: CD28 and c-Rel-Dependent Pathways Initiate Regulatory T Cell Development. The Journal of Immunology, 184, 4074-4077.
https://doi.org/10.4049/jimmunol.0903933
[60]  Lio, C.W., Dodson, L.F., Deppong, C.M., Hsieh, C.S. and Green, J.M. (2010) CD28 Facilitates the Generation of Foxp3(-) Cytokine Responsive Regulatory T Cell Precursors. The Journal of Immunology, 184, 6007-6013.
https://doi.org/10.4049/jimmunol.1000019
[61]  Malek, T.R., Yu, A., Vincek, V., Scibelli, P. and Kong, L. (2002) CD4 Regulatory T Cells Prevent Lethal Autoimmunity in IL-2Rbeta-Deficient Mice. Implications for the Nonredundant Function of IL-2. Immunity, 17, 167-178.
https://doi.org/10.1016/S1074-7613(02)00367-9
[62]  Suzuki, H., et al. (1995) Deregulated T Cell Activation and Autoimmunity in Mice Lacking Interleukin-2 Receptor Beta. Science, 268, 1472-1476.
https://doi.org/10.1126/science.7770771
[63]  Zorn, E., et al. (2006) IL-2 Regulates FOXP3 Expression in Human CD4+ CD25+ Regulatory T Cells through a STAT-Dependent Mechanism and Induces the Expansion of These Cells in Vivo. Blood, 108, 1571-1579.
https://doi.org/10.1182/blood-2006-02-004747
[64]  Wirnsberger, G., Mair, F. and Klein, L. (2009) Regulatory T Cell Differentiation of Thymocytes Does Not Require a Dedicated Antigen-Presenting Cell But Is under T Cell-Intrinsic Developmental Control. Proceedings of the National Academy of Sciences, 106, 10278-10283.
https://doi.org/10.1073/pnas.0901877106
[65]  Isomura, I., et al. (2009) c-Rel Is Required for the Development of Thymic Foxp3+ CD4 Regulatory T Cells. The Journal of Experimental Medicine, 206, 3001-3014.
https://doi.org/10.1084/jem.20091411
[66]  Hori, S. (2010) c-Rel: A Pioneer in Directing Regulatory T-Cell Lineage Commitment? European Journal of Immunology, 40, 664-667.
https://doi.org/10.1002/eji.201040372
[67]  Marie, J.C., Letterio, J.J., Gavin, M. and Rudensky, A.Y. (2005) TGF-beta1 Maintains Suppressor Function and Foxp3 Expression in CD4+ CD25+ Regulatory T Cells. The Journal of Experimental Medicine, 201, 1061-1067.
https://doi.org/10.1084/jem.20042276
[68]  Li, M.O., Sanjabi, S. and Flavell, R.A. (2006) Transforming Growth Factor-Beta Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms. Immunity, 25, 455-471.
https://doi.org/10.1016/j.immuni.2006.07.011
[69]  Nazzal, D., Gradolatto, A., Truffault, F., Bismuth, J. and Berrih-Aknin, S. (2014) Human Thymus Medullary Epithelial Cells Promote Regulatory T-Cell Generation by Stimulating Interleukin-2 Production via ICOS Ligand. Cell Death & Disease, 5, e1420.
https://doi.org/10.1038/cddis.2014.377
[70]  Chen, W., et al. (2003) Conversion of Peripheral CD4+ CD25-Naive T Cells to CD4+ CD25+ Regulatory T Cells by TGF-Beta Induction of Transcription Factor Foxp3. The Journal of Experimental Medicine, 198, 1875-1886.
https://doi.org/10.1084/jem.20030152
[71]  Lan, R.Y., Ansari, A.A., Lian, Z.X. and Gershwin, M.E. (2005) Regulatory T Cells: Development, Function and Role in Autoimmunity. Autoimmunity Reviews, 4, 351-363.
https://doi.org/10.1016/j.autrev.2005.01.007
[72]  Zheng, S.G. (2013) Regulatory T Cells vs. Th17: Differentiation of Th17 versus Treg, Are the Mutually Exclusive? American Journal of Clinical and Experimental Immunology, 2, 94-106.
[73]  Chai, J.N., Zhou, Y.W. and Hsieh, C.S. (2014) T Cells and Intestinal Commensal Bacteria—Ignorance, Rejection, and Acceptance. FEBS Letters, 588, 4167-4175.
https://doi.org/10.1016/j.febslet.2014.06.040
[74]  Yuan, X., Cheng, G. and Malek, T.R. (2014) The Importance of Regulatory T-Cell Heterogeneity in Maintaining Self-Tolerance. Immunological Reviews, 259, 103-114.
https://doi.org/10.1111/imr.12163
[75]  Gobert, M. and Lafaille, J.J. (2012) Maternal-Fetal Immune Tolerance, Block by Block. Cell, 150, 7-9.
https://doi.org/10.1016/j.cell.2012.06.020
[76]  Fu, S., et al. (2004) TGF-Beta Induces Foxp3+ T-Regulatory Cells from CD4+ CD25-Precursors. American Journal of Transplantation, 4, 1614-1627.
https://doi.org/10.1111/j.1600-6143.2004.00566.x
[77]  Horwitz, D.A., Zheng, S.G. and Gray, J.D. (2003) The Role of the Combination of IL-2 and TGF-Beta or IL-10 in the Generation and Function of CD4+ CD25+ and CD8+ Regulatory T Cell Subsets. Journal of Leukocyte Biology, 74, 471-478.
https://doi.org/10.1189/jlb.0503228
[78]  Yamagiwa, S., Gray, J.D., Hashimoto, S. and Horwitz, D.A. (2001) A Role for TGF-Beta in the Generation and Expansion of CD4+ CD25+ Regulatory T Cells from Human Peripheral Blood. The Journal of Immunology, 166, 7282-7289.
https://doi.org/10.4049/jimmunol.166.12.7282
[79]  Rudensky, A.Y. and Campbell, D.J. (2006) In Vivo Sites and Cellular Mechanisms of T Reg Cell-Mediated Suppression. The Journal of Experimental Medicine, 203, 489-492.
https://doi.org/10.1084/jem.20060214
[80]  Bluestone, J.A. and Abbas, A.K. (2003) Natural versus Adaptive Regulatory T Cells. Nature Reviews Immunology, 3, 253-257.
https://doi.org/10.1038/nri1032
[81]  Whiteside, T.L. (2014) Induced Regulatory T Cells in Inhibitory Microenvironments Created by Cancer. Expert Opinion on Biological Therapy, 14, 1411-1425.
https://doi.org/10.1517/14712598.2014.927432
[82]  Lu, L., et al. (2010) Synergistic Effect of TGF-Beta Superfamily Members on the Induction of Foxp3+ Treg. European Journal of Immunology, 40, 142-152.
https://doi.org/10.1002/eji.200939618
[83]  Lu, L., et al. (2010) Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells. The Journal of Immunology, 184, 4295-4306.
https://doi.org/10.4049/jimmunol.0903418
[84]  Zhou, X., et al. (2010) Isolation of Purified and Live Foxp3+ Regulatory T Cells Using FACS Sorting on Scatter Plot. Journal of Molecular Cell Biology, 2, 164-169.
https://doi.org/10.1093/jmcb/mjq007
[85]  Chalmin, F., et al. (2012) Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression. Immunity, 36, 362-373.
https://doi.org/10.1016/j.immuni.2011.12.019
[86]  Li, C., Ebert, P.J. and Li, Q.J. (2013) T Cell Receptor (TCR) and Transforming Growth Factor Beta (TGF-Beta) Signaling Converge on DNA (Cytosine-5)-Methyltransferase to Control Forkhead Box Protein 3 (Foxp3) Locus Methylation and Inducible Regulatory T Cell Differentiation. The Journal of Biological Chemistry, 288, 19127-19139.
https://doi.org/10.1074/jbc.M113.453357
[87]  Yadav, M., Stephan, S. and Bluestone, J.A. (2013) Peripherally Induced Tregs-Role in Immune Homeostasis and Autoimmunity. Frontiers in Immunology, 4, 232.
https://doi.org/10.3389/fimmu.2013.00232
[88]  Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X.P., Forbush, K. and Rudensky, A.Y. (2010) Role of Conserved Non-Coding DNA Elements in the Foxp3 Gene in Regulatory T-Cell Fate. Nature, 463, 808-812.
https://doi.org/10.1038/nature08750
[89]  Zheng, S.G., Wang, J., Wang, P., Gray, J.D. and Horwitz, D.A. (2007) IL-2 Is Essential for TGF-Beta to Convert Naive CD4+ CD25-Cells to CD25+ Foxp3+ Regulatory T Cells and for Expansion of These Cells. The Journal of Immunology, 178, 2018-2027.
https://doi.org/10.4049/jimmunol.178.4.2018
[90]  Lu, L., et al. (2011) All-Trans Retinoic Acid Promotes TGF-Beta-Induced Tregs via Histone Modification But Not DNA Demethylation on Foxp3 Gene Locus. PLoS ONE, 6, e24590.
https://doi.org/10.1371/journal.pone.0024590
[91]  Shi, Q., et al. (2011) CD4+ Foxp3+ Regulatory T Cells Induced by TGF-Beta, IL-2 and All-Trans Retinoic Acid Attenuate Obliterative Bronchiolitis in Rat Trachea Transplantation. International Immunopharmacology, 11, 1887-1894.
https://doi.org/10.1016/j.intimp.2011.07.020
[92]  Laurence, A., et al. (2007) Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation. Immunity, 26, 371-381.
https://doi.org/10.1016/j.immuni.2007.02.009
[93]  Burchill, M.A., Yang, J., Vogtenhuber, C., Blazar, B.R. and Farrar, M.A. (2007) IL-2 Receptor Beta-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells. The Journal of Immunology, 178, 280-290.
https://doi.org/10.4049/jimmunol.178.1.280
[94]  Brandenburg, S., et al. (2008) IL-2 Induces in Vivo Suppression by CD4(+) CD25(+) Foxp3(+) Regulatory T Cells. European Journal of Immunology, 38, 1643-1653.
https://doi.org/10.1002/eji.200737791
[95]  Hall, J.A., Grainger, J.R., Spencer, S.P. and Belkaid, Y. (2011) The Role of Retinoic Acid in Tolerance and Immunity. Immunity, 35, 13-22.
https://doi.org/10.1016/j.immuni.2011.07.002
[96]  Maruyama, T., Konkel, J.E., Zamarron, B.F. and Chen, W. (2011) The Molecular Mechanisms of Foxp3 Gene Regulation. Seminars in Immunology, 23, 418-423.
https://doi.org/10.1016/j.smim.2011.06.005
[97]  Xiao, S., et al. (2008) Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-Beta-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression. The Journal of Immunology, 181, 2277-2284.
https://doi.org/10.4049/jimmunol.181.4.2277
[98]  Nolting, J., et al. (2009) Retinoic Acid Can Enhance Conversion of Naive into Regulatory T Cells Independently of Secreted Cytokines. The Journal of Experimental Medicine, 206, 2131-2139.
https://doi.org/10.1084/jem.20090639
[99]  Yoshimura, A. and Muto, G. (2011) TGF-Beta Function in Immune Suppression. Current Topics in Microbiology and Immunology, 350, 127-147.
https://doi.org/10.1007/82_2010_87
[100]  Takimoto, T., et al. (2010) Smad2 and Smad3 Are Redundantly Essential for the TGF-Beta-Mediated Regulation of Regulatory T Plasticity and Th1 Development. The Journal of Immunology, 185, 842-855.
https://doi.org/10.4049/jimmunol.0904100
[101]  Luckheeram, R.V., Zhou, R., Verma, A.D. and Xia, B. (2012) CD4(+) T Cells: Differentiation and Functions. Clinical & Developmental Immunology, 2012, Article ID: 925135.
https://doi.org/10.1155/2012/925135
[102]  Couper, K.N., et al. (2008) IL-10 from CD4CD25Foxp3CD127 Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection. PLOS Pathogens, 4, e1000004.
https://doi.org/10.1371/journal.ppat.1000004
[103]  Fujio, K., Okamura, T. and Yamamoto, K. (2010) The Family of IL-10-Secreting CD4+ T Cells. Advances in Immunology, 105, 99-130.
https://doi.org/10.1016/S0065-2776(10)05004-2
[104]  Roncarolo, M.G., et al. (2006) Interleukin-10-Secreting Type 1 Regulatory T Cells in Rodents and Humans. Immunological Reviews, 212, 28-50.
https://doi.org/10.1111/j.0105-2896.2006.00420.x
[105]  Awasthi, A., et al. (2007) A Dominant Function for Interleukin 27 in Generating Interleukin 10-Producing Anti-Inflammatory T Cells. Nature Immunology, 8, 1380-1389.
https://doi.org/10.1038/ni1541
[106]  Gregori, S., et al. (2010) Differentiation of Type 1 T Regulatory Cells (Tr1) by Tolerogenic DC-10 Requires the IL-10-Dependent ILT4/HLA-G Pathway. Blood, 116, 935-944.
https://doi.org/10.1182/blood-2009-07-234872
[107]  Pot, C., et al. (2009) Cutting Edge: IL-27 Induces the Transcription Factor c-Maf, Cytokine IL-21, and the Costimulatory Receptor ICOS That Coordinately Act Together to Promote Differentiation of IL-10-Producing Tr1 Cells. The Journal of Immunology, 183, 797-801.
https://doi.org/10.4049/jimmunol.0901233
[108]  Quintana, F.J. and Sherr, D.H. (2013) Aryl Hydrocarbon Receptor Control of Adaptive Immunity. Pharmacological Reviews, 65, 1148-1161.
https://doi.org/10.1124/pr.113.007823
[109]  Apetoh, L., et al. (2010) The Aryl Hydrocarbon Receptor Interacts with c-Maf to Promote the Differentiation of Type 1 Regulatory T Cells Induced by IL-27. Nature Immunology, 11, 854-861.
https://doi.org/10.1038/ni.1912
[110]  Walsh, P.T., Taylor, D.K. and Turka, L.A. (2004) Tregs and Transplantation Tolerance. Journal of Clinical Investigation, 114, 1398-1403.
https://doi.org/10.1172/JCI200423238
[111]  Korn, T., Bettelli, E., Oukka, M. and Kuchroo, V.K. (2009) IL-17 and Th17 Cells. Annual Review of Immunology, 27, 485-517.
https://doi.org/10.1146/annurev.immunol.021908.132710
[112]  Nistala, K. and Wedderburn, L.R. (2009) Th17 and Regulatory T Cells: Rebalancing Pro- and Anti-Inflammatory Forces in Autoimmune Arthritis. Rheumatology (Oxford), 48, 602-606.
https://doi.org/10.1093/rheumatology/kep028
[113]  Collison, L.W., et al. (2010) IL-35-Mediated Induction of a Potent Regulatory T Cell Population. Nature Immunology, 11, 1093-1101.
https://doi.org/10.1038/ni.1952
[114]  Roncarolo, M.G., Bacchetta, R., Bordignon, C., Narula, S. and Levings, M.K. (2001) Type 1 T Regulatory Cells. Immunological Reviews, 182, 68-79.
https://doi.org/10.1034/j.1600-065X.2001.1820105.x
[115]  Weiner, H.L. (2001) Induction and Mechanism of Action of Transforming Growth Factor-Beta-Secreting Th3 Regulatory Cells. Immunological Reviews, 182, 207-214.
https://doi.org/10.1034/j.1600-065X.2001.1820117.x
[116]  Vieira, P.L., et al. (2004) IL-10-Secreting Regulatory T Cells Do Not Express Foxp3 But Have Comparable Regulatory Function to Naturally Occurring CD4+ CD25+ Regulatory T Cells. The Journal of Immunology, 172, 5986-5993.
https://doi.org/10.4049/jimmunol.172.10.5986
[117]  Passerini, L., et al. (2011) Functional Type 1 Regulatory T Cells Develop Regardless of FOXP3 Mutations in Patients with IPEX Syndrome. European Journal of Immunology, 41, 1120-1131.
https://doi.org/10.1002/eji.201040909
[118]  Levings, M.K. and Roncarolo, M.G. (2005) Phenotypic and Functional Differences between Human CD4+ CD25+ and Type 1 Regulatory T Cells. Current Topics in Microbiology and Immunology, 293, 303-326.
https://doi.org/10.1007/3-540-27702-1_14
[119]  Gol-Ara, M., Jadidi-Niaragh, F., Sadria, R., Azizi, G. and Mirshafiey, A. (2012) The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis. Arthritis, 2012, Article ID: 805875.
https://doi.org/10.1155/2012/805875
[120]  Jankovic, D., et al. (2007) Conventional T-bet(+)Foxp3(-) Th1 Cells Are the Major Source of Host-Protective Regulatory IL-10 during Intracellular Protozoan Infection. The Journal of Experimental Medicine, 204, 273-283.
https://doi.org/10.1084/jem.20062175
[121]  Peterson, R.A. (2012) Regulatory T-Cells: Diverse Phenotypes Integral to Immune Homeostasis and Suppression. Toxicologic Pathology, 40, 186-204.
https://doi.org/10.1177/0192623311430693
[122]  Crome, S.Q., Wang, A.Y. and Levings, M.K. (2010) Translational Mini-Review Series on Th17 Cells: Function and Regulation of Human T Helper 17 Cells in Health and Disease. Clinical & Experimental Immunology, 159, 109-119.
https://doi.org/10.1111/j.1365-2249.2009.04037.x
[123]  Nakagawa, T., et al. (2010) IL-6 Positively Regulates Foxp3+ CD8+ T Cells in Vivo. International Immunology, 22, 129-139.
https://doi.org/10.1093/intimm/dxp119
[124]  Thornton, A.M., et al. (2010) Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells. The Journal of Immunology, 184, 3433-3441.
https://doi.org/10.4049/jimmunol.0904028
[125]  Lin, X., et al. (2013) Advances in Distinguishing Natural from Induced Foxp3(+) Regulatory T Cells. International Journal of Clinical and Experimental Pathology, 6, 116-123.
[126]  Akimova, T., Beier, U.H., Wang, L., Levine, M.H. and Hancock, W.W. (2011) Helios Expression Is a Marker of T Cell Activation and Proliferation. PLoS ONE, 6, e24226.
https://doi.org/10.1371/journal.pone.0024226
[127]  Serre, K., et al. (2011) Helios Is Associated with CD4 T Cells Differentiating to T Helper 2 and Follicular Helper T Cells in Vivo Independently of Foxp3 Expression. PLoS ONE, 6, e20731.
https://doi.org/10.1371/journal.pone.0020731
[128]  Gottschalk, R.A., Corse, E. and Allison, J.P. (2012) Expression of Helios in Peripherally Induced Foxp3+ Regulatory T Cells. The Journal of Immunology, 188, 976-980.
https://doi.org/10.4049/jimmunol.1102964
[129]  Ross, E.M., et al. (2014) Helios Defines T Cells Being Driven to Tolerance in the Periphery and Thymus. European Journal of Immunology, 44, 2048-2058.
https://doi.org/10.1002/eji.201343999
[130]  Yadav, M., et al. (2012) Neuropilin-1 Distinguishes Natural and Inducible Regulatory T Cells among Regulatory T Cell Subsets in Vivo. The Journal of Experimental Medicine, 209, 1713-1722.
https://doi.org/10.1084/jem.20120822
[131]  Hansen, W., et al. (2012) Neuropilin 1 Deficiency on CD4+ Foxp3+ Regulatory T Cells Impairs Mouse Melanoma Growth. The Journal of Experimental Medicine, 209, 2001-2016.
https://doi.org/10.1084/jem.20111497
[132]  Milpied, P., et al. (2009) Neuropilin-1 Is Not a Marker of Human Foxp3+ Treg. European Journal of Immunology, 39, 1466-1471.
https://doi.org/10.1002/eji.200839040
[133]  Dhamne, C., Chung, Y., Alousi, A.M., Cooper, L.J.N. and Tran, D.Q. (2013) Peripheral and Thymic Foxp3(+) Regulatory T Cells in Search of Origin, Distinction, and Function. Frontiers in Immunology, 4, 253.
https://doi.org/10.3389/fimmu.2013.00253
[134]  Tran, D.Q., et al. (2009) Selective Expression of Latency-Associated Peptide (LAP) and IL-1 Receptor Type I/II (CD121a/CD121b) on Activated Human FOXP3+ Regulatory T Cells Allows for Their Purification from Expansion Cultures. Blood, 113, 5125-5133.
https://doi.org/10.1182/blood-2009-01-199950
[135]  Pabbisetty, S.K., et al. (2014) KLF2 Is a Rate-Limiting Transcription Factor That Can Be Targeted to Enhance Regulatory T-Cell Production. Proceedings of the National Academy of Sciences, 111, 9579-9584.
https://doi.org/10.1073/pnas.1323493111
[136]  Suffia, I.J., Reckling, S.K., Piccirillo, C.A., Goldszmid, R.S. and Belkaid, Y. (2006) Infected Site-Restricted Foxp3+ Natural Regulatory T Cells Are Specific for Microbial Antigens. The Journal of Experimental Medicine, 203, 777-788.
https://doi.org/10.1084/jem.20052056
[137]  Bettini, M. and Vignali, D.A. (2009) Regulatory T Cells and Inhibitory Cytokines in Autoimmunity. Current Opinion in Immunology, 21, 612-618.
https://doi.org/10.1016/j.coi.2009.09.011
[138]  McGeachy, M.J., Stephens, L.A. and Anderton, S.M. (2005) Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+ CD25+ Regulatory Cells within the Central Nervous System. The Journal of Immunology, 175, 3025-3032.
https://doi.org/10.4049/jimmunol.175.5.3025
[139]  Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L. and Powrie, F. (1999) An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation. The Journal of Experimental Medicine, 190, 995-1004.
https://doi.org/10.1084/jem.190.7.995
[140]  Annacker, O., Asseman, C., Read, S. and Powrie, F. (2003) Interleukin-10 in the Regulation of T Cell-Induced Colitis. Journal of Autoimmunity, 20, 277-279.
https://doi.org/10.1016/S0896-8411(03)00045-3
[141]  Joetham, A., et al. (2007) Naturally Occurring Lung CD4(+)CD25(+) T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-Beta. The Journal of Immunology, 178, 1433-1442.
https://doi.org/10.4049/jimmunol.178.3.1433
[142]  Rubtsov, Y.P., et al. (2008) Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces. Immunity, 28, 546-558.
https://doi.org/10.1016/j.immuni.2008.02.017
[143]  Li, M.O., Wan, Y.Y. and Flavell, R.A. (2007) T Cell-Produced Transforming Growth Factor-Beta1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation. Immunity, 26, 579-591.
https://doi.org/10.1016/j.immuni.2007.03.014
[144]  Zhang, Q., et al. (2006) Blockade of Transforming Growth Factor-Beta Signaling in Tumor-Reactive CD8(+) T Cells Activates the Antitumor Immune Response Cycle. Molecular Cancer Therapeutics, 5, 1733-1743.
https://doi.org/10.1158/1535-7163.MCT-06-0109
[145]  Shevach, E.M., Tran, D.Q., Davidson, T.S. and Andersson, J. (2008) The Critical Contribution of TGF-Beta to the Induction of Foxp3 Expression and Regulatory T Cell Function. European Journal of Immunology, 38, 915-917.
https://doi.org/10.1002/eji.200738111
[146]  Andersson, J., et al. (2008) CD4+ FoxP3+ Regulatory T Cells Confer Infectious Tolerance in a TGF-Beta-Dependent Manner. The Journal of Experimental Medicine, 205, 1975-1981.
https://doi.org/10.1084/jem.20080308
[147]  Piccirillo, C.A., et al. (2002) CD4(+)CD25(+) Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor Beta1 Production and Responsiveness. The Journal of Experimental Medicine, 196, 237-246.
https://doi.org/10.1084/jem.20020590
[148]  Collison, L.W., et al. (2007) The Inhibitory Cytokine IL-35 Contributes to Regulatory T-Cell Function. Nature, 450, 566-569.
https://doi.org/10.1038/nature06306
[149]  Chaturvedi, V., Collison, L.W., Guy, C.S., Workman, C.J. and Vignali, D.A. (2011) Cutting Edge: Human Regulatory T Cells Require IL-35 to Mediate Suppression and Infectious Tolerance. The Journal of Immunology, 186, 6661-6666.
https://doi.org/10.4049/jimmunol.1100315
[150]  Veldhoen, M., et al. (2006) Modulation of Dendritic Cell Function by Naive and Regulatory CD4+ T Cells. The Journal of Immunology, 176, 6202-6210.
https://doi.org/10.4049/jimmunol.176.10.6202
[151]  Houot, R., Perrot, I., Garcia, E., Durand, I. and Lebecque, S. (2006) Human CD4+ CD25 High Regulatory T Cells Modulate Myeloid But Not Plasmacytoid Dendritic Cells Activation. The Journal of Immunology, 176, 5293-5298.
https://doi.org/10.4049/jimmunol.176.9.5293
[152]  Wing, K., et al. (2008) CTLA-4 Control over Foxp3+ Regulatory T Cell Function. Science, 322, 271-275.
https://doi.org/10.1126/science.1160062
[153]  Oderup, C., Cederbom, L., Makowska, A., Cilio, C.M. and Ivars, F. (2006) Cytotoxic T Lymphocyte Antigen-4-Dependent Down-Modulation of Costimulatory Molecules on Dendritic Cells in CD4+ CD25+ Regulatory T-Cell-Mediated Suppression. Immunology, 118, 240-249.
https://doi.org/10.1111/j.1365-2567.2006.02362.x
[154]  Read, S., et al. (2006) Blockade of CTLA-4 on CD4+ CD25+ Regulatory T Cells Abrogates Their Function in Vivo. The Journal of Immunology, 177, 4376-4383.
https://doi.org/10.4049/jimmunol.177.7.4376
[155]  Takahashi, T., et al. (2000) Immunologic Self-Tolerance Maintained by CD25(+) CD4(+) Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte-Associated Antigen 4. The Journal of Experimental Medicine, 192, 303-310.
https://doi.org/10.1084/jem.192.2.303
[156]  Friedline, R.H., et al. (2009) CD4+ Regulatory T Cells Require CTLA-4 for the Maintenance of Systemic Tolerance. The Journal of Experimental Medicine, 206, 421-434.
https://doi.org/10.1084/jem.20081811
[157]  Puccetti, P. and Grohmann, U. (2007) IDO and Regulatory T Cells: A Role for Reverse Signalling and Non-Canonical NF-kappaB Activation. Nature Reviews Immunology, 7, 817-823.
https://doi.org/10.1038/nri2163
[158]  Mbongue, J.C., et al. (2015) The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity. Vaccines (Basel), 3, 703-729.
https://doi.org/10.3390/vaccines3030703
[159]  Dejean, A.S., Hedrick, S.M. and Kerdiles, Y.M. (2011) Highly Specialized Role of Forkhead Box O Transcription Factors in the Immune System. Antioxid Redox Signal, 14, 663-674.
https://doi.org/10.1089/ars.2010.3414
[160]  Liang, B., et al. (2008) Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II. The Journal of Immunology, 180, 5916-5926.
https://doi.org/10.4049/jimmunol.180.9.5916
[161]  Goldberg, M.V. and Drake, C.G. (2011) LAG-3 in Cancer Immunotherapy. Current Topics in Microbiology and Immunology, 344, 269-278.
https://doi.org/10.1007/82_2010_114
[162]  Holst, J., et al. (2008) Scalable Signaling Mediated by T Cell Antigen Receptor-CD3 ITAMs Ensures Effective Negative Selection and Prevents Autoimmunity. Nature Immunology, 9, 658-666.
https://doi.org/10.1038/ni.1611
[163]  Shalev, I., et al. (2008) Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis. The Journal of Immunology, 180, 249-260.
https://doi.org/10.4049/jimmunol.180.1.249
[164]  Huang, C.T., et al. (2004) Role of LAG-3 in Regulatory T Cells. Immunity, 21, 503-513.
https://doi.org/10.1016/j.immuni.2004.08.010
[165]  Chattopadhyay, G. and Shevach, E.M. (2013) Antigen-Specific Induced T Regulatory Cells Impair Dendritic Cell Function via an IL-10/MARCH1-Dependent Mechanism. The Journal of Immunology, 191, 5875-5884.
https://doi.org/10.4049/jimmunol.1301693
[166]  Bartee, E., Mansouri, M., Hovey Nerenberg, B.T., Gouveia, K. and Früh, K. (2004) Down-Regulation of Major Histocompatibility Complex Class I by Human Ubiquitin Ligases Related to Viral Immune Evasion Proteins. Journal of Virology, 78, 1109-1120.
https://doi.org/10.1128/JVI.78.3.1109-1120.2004
[167]  Tze, L.E., et al. (2011) CD83 Increases MHC II and CD86 on Dendritic Cells by Opposing IL-10-Driven MARCH1-Mediated Ubiquitination and Degradation. The Journal of Experimental Medicine, 208, 149-165.
https://doi.org/10.1084/jem.20092203
[168]  Vignali, D.A., Collison, L.W. and Workman, C.J. (2008) How Regulatory T Cells Work. Nature Reviews Immunology, 8, 523-532.
https://doi.org/10.1038/nri2343
[169]  Woo, S.R., et al. (2012) Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-Cell Function to Promote Tumoral Immune Escape. Cancer Research, 72, 917-927.
https://doi.org/10.1158/0008-5472.CAN-11-1620
[170]  Nguyen, L.T. and Ohashi, P.S. (2015) Clinical Blockade of PD1 and LAG3—Potential Mechanisms of Action. Nature Reviews Immunology, 15, 45-56.
https://doi.org/10.1038/nri3790
[171]  Riella, L.V., Paterson, A.M., Sharpe, A.H. and Chandraker, A. (2012) Role of the PD-1 Pathway in the Immune Response. American Journal of Transplantation, 12, 2575-2587.
https://doi.org/10.1111/j.1600-6143.2012.04224.x
[172]  Pardoll, D.M. (2012) The Blockade of Immune Checkpoints in Cancer Immunotherapy. Nature Reviews Cancer, 12, 252-264.
https://doi.org/10.1038/nrc3239
[173]  Janssens, W., et al. (2003) CD4+ CD25+ T Cells Lyse Antigen-Presenting B Cells by Fas-Fas Ligand Interaction in an Epitope-Specific Manner. The Journal of Immunology, 171, 4604-4612.
https://doi.org/10.4049/jimmunol.171.9.4604
[174]  Grossman, W.J., Verbsky, J.W., Barchet, W., Colonna, M., Atkinson, J.P. and Ley, T.J. (2004) Human T Regulatory Cells Can Use the Perforin Pathway to Cause Autologous Target Cell Death. Immunity, 21, 589-601.
https://doi.org/10.1016/j.immuni.2004.09.002
[175]  Grossman, W.J., Verbsky, J.W., Tollefsen, B.L., Kemper, C., Atkinson, J.P. and Ley, T.J. (2004) Differential Expression of Granzymes A and B in Human Cytotoxic Lymphocyte Subsets and T Regulatory Cells. Blood, 104, 2840-2848.
https://doi.org/10.1182/blood-2004-03-0859
[176]  Gondek, D.C., Lu, L.F., Quezada, S.A., Sakaguchi, S. and Noelle, R.J. (2005) Cutting Edge: Contact-Mediated Suppression by CD4+ CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism. The Journal of Immunology, 174, 1783-1786.
[177]  Sojka, D.K., Huang, Y.H. and Fowell, D.J. (2008) Mechanisms of Regulatory T-Cell Suppression—A Diverse Arsenal for a Moving Target. Immunology, 124, 13-22.
https://doi.org/10.1111/j.1365-2567.2008.02813.x
[178]  Cao, X., et al. (2007) Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance. Immunity, 27, 635-646.
https://doi.org/10.1016/j.immuni.2007.08.014
[179]  Fontenot, J.D., Rasmussen, J.P., Gavin, M.A. and Rudensky, A.Y. (2005) A Function for Interleukin 2 in Foxp3-Expressing Regulatory T Cells. Nature Immunology, 6, 1142-1151.
https://doi.org/10.1038/ni1263
[180]  Huibregtse, I.L., van Lent, A.U. and van Deventer, S.J. (2007) Immunopathogenesis of IBD: Insufficient Suppressor Function in the Gut? Gut, 56, 584-592.
https://doi.org/10.1136/gut.2006.103523
[181]  Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. and Yamaguchi, T. (2009) Regulatory T Cells: How Do They Suppress Immune Responses? International Immunology, 21, 1105-1111.
https://doi.org/10.1093/intimm/dxp095
[182]  Schmidt, A., Oberle, N. and Krammer, P.H. (2012) Molecular Mechanisms of Treg-Mediated T Cell Suppression. Frontiers in Immunology, 3, 51.
https://doi.org/10.3389/fimmu.2012.00051
[183]  Longhi, M.S., Robson, S.C., Bernstein, S.H., Serra, S. and Deaglio, S. (2013) Biological Functions of Ecto-Enzymes in Regulating Extracellular Adenosine Levels in Neoplastic and Inflammatory Disease States. Journal of Molecular Medicine, 91, 165-172.
https://doi.org/10.1007/s00109-012-0991-z
[184]  Ayyoub, M., et al. (2009) Human Memory FOXP3+ Tregs Secrete IL-17 ex Vivo and Constitutively Express the T(H)17 Lineage-Specific Transcription Factor RORgamma t. Proceedings of the National Academy of Sciences, 106, 8635-8640.
https://doi.org/10.1073/pnas.0900621106
[185]  Beriou, G., et al. (2009) IL-17-Producing Human Peripheral Regulatory T Cells Retain Suppressive Function. Blood, 113, 4240-4249.
https://doi.org/10.1182/blood-2008-10-183251
[186]  Zheng, Y., et al. (2009) Regulatory T-Cell Suppressor Program Co-Opts Transcription Factor IRF4 to Control T(H)2 Responses. Nature, 458, 351-356.
https://doi.org/10.1038/nature07674
[187]  Koch, M.A., Thomas, K.R., Perdue, N.R., Smigiel, K.S., Srivastava, S. and Campbell, D.J. (2012) T-bet(+) Treg Cells Undergo Abortive Th1 Cell Differentiation Due to Impaired Expression of IL-12 Receptor beta2. Immunity, 37, 501-510.
https://doi.org/10.1016/j.immuni.2012.05.031
[188]  Linterman, M.A., Liston, A. and Vinuesa, C.G. (2012) T-Follicular Helper Cell Differentiation and the Co-Option of This Pathway by Non-Helper Cells. Immunological Reviews, 247, 143-159.
https://doi.org/10.1111/j.1600-065X.2012.01121.x
[189]  Kroenke, M.A., et al. (2012) Bcl6 and Maf Cooperate to Instruct Human Follicular Helper CD4 T Cell Differentiation. The Journal of Immunology, 188, 3734-3744.
https://doi.org/10.4049/jimmunol.1103246
[190]  Liu, X., et al. (2012) Bcl6 Expression Specifies the T Follicular Helper Cell Program in Vivo. The Journal of Experimental Medicine, 209, 1841-1852.
https://doi.org/10.1084/jem.20120219
[191]  Perreau, M., et al. (2013) Follicular Helper T Cells Serve as the Major CD4 T Cell Compartment for HIV-1 Infection, Replication, and Production. The Journal of Experimental Medicine, 210, 143-156.
https://doi.org/10.1084/jem.20121932
[192]  Matsushita, N., et al. (2008) Comparative Methodologies of Regulatory T Cell Depletion in a Murine Melanoma Model. The Journal of Immunology Methods, 333, 167-179.
https://doi.org/10.1016/j.jim.2008.01.012
[193]  Lahl, K. and Sparwasser, T. (2011) In Vivo Depletion of FoxP3+ Tregs Using the DEREG Mouse Model. Methods in Molecular Biology, 707, 157-172.
https://doi.org/10.1007/978-1-61737-979-6_10
[194]  Kim, J.M., Rasmussen, J.P. and Rudensky, A.Y. (2007) Regulatory T Cells Prevent Catastrophic Autoimmunity throughout the Lifespan of Mice. Nature Immunology, 8, 191-197.
https://doi.org/10.1038/ni1428
[195]  Suffner, J., et al. (2010) Dendritic Cells Support Homeostatic Expansion of Foxp3+ Regulatory T Cells in Foxp3.LuciDTR Mice. The Journal of Immunology, 184, 1810-1820.
https://doi.org/10.4049/jimmunol.0902420
[196]  Lahl, K., et al. (2007) Selective Depletion of Foxp3+ Regulatory T Cells Induces a Scurfy-Like Disease. The Journal of Experimental Medicine, 204, 57-63.
https://doi.org/10.1084/jem.20061852

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