| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles
1Correspondence: University of Southern California, Keck School of Medicine, Division of Rheumatology and Immunology, 2011 Zonal Avenue, HMR 711, Los Angeles, CA 90033-1034. E-mail: dhorwitz{at}hsc.usc.edu
Recently, considerable attention has been focused on thymus-derived CD4+ regulatory T cells that constitutively express CD25 and have a contact-dependent, cytokine-independent mechanism in vitro. However, peripheral CD4+ and CD8+ T cells can also be induced to become regulatory T cells. Here we review our studies using the combination of IL-2 and transforming growth factor ß (TGF-ß) to generate regulatory T cell subsets ex vivo, and the work of others using IL-10 to induce suppressive activity. Under certain conditions, the autocrine effects of TGF-ß and IL-10 induce peripheral T cells to produce immunosuppressive levels of each of these cytokines. This effect of TGF-ß is IL-2 dependent. Under other conditions IL-2 and TGF-ß can induce CD4+ cells to develop potent contact-dependent, cytokine-independent regulatory activity. At present, there is considerable confusion concerning the mechanism of action of CD4+ CD25+ cells because cytokine-producing regulatory T cells generated in the periphery can express CD25 and other markers displayed by naturally occurring, thymus-derived regulatory T cells. We, therefore, propose a nomenclature that identifies thymus-derived and peripheral regulatory cells, and that also differentiates T regulatory cells from T helper cells. Because T regulatory cells broadly control T helper cell reactivity, the mechanisms that control regulatory cell function are also reviewed. Finally, the potential use of regulatory T cells generated ex vivo as an adoptive immunotherapy for certain autoimmune diseases, to prevent organ graft rejection, or to prevent pathologic host responses to infectious agents is discussed.
Key Words: IL-10 • TGF-Beta • IL-2 • autoimmunity • CD4+ CD25+ • regulatory cells
This article has been cited by other articles:
|
|
 |
|
  M. Kovar, J. Tomala, H. Chmelova, L. Kovar, T. Mrkvan, R. Joskova, Z. Zakostelska, T. Etrych, J. Strohalm, K. Ulbrich, et al. Overcoming Immunoescape Mechanisms of BCL1 Leukemia and Induction of CD8+ T-Cell-Mediated BCL1-Specific Resistance in Mice Cured by Targeted Polymer-Bound Doxorubicin Cancer Res., December 1, 2008; 68(23): 9875 - 9883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Simone, A. Zicca, and D. Saverino The frequency of regulatory CD3+CD8+CD28-CD25+ T lymphocytes in human peripheral blood increases with age J. Leukoc. Biol., December 1, 2008; 84(6): 1454 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dolganiuc and G. Szabo T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't J. Leukoc. Biol., September 1, 2008; 84(3): 614 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sharabi and E. Mozes The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells J. Immunol., September 1, 2008; 181(5): 3243 - 3251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Passerini, S. E. Allan, M. Battaglia, S. Di Nunzio, A. N. Alstad, M. K. Levings, M. G. Roncarolo, and R. Bacchetta STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells Int. Immunol., March 1, 2008; 20(3): 421 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hu, R. S. Arias, R. E. Sadun, Y.-C. Nien, N. Zhang, H. Sabzevari, M.E. C. Lutsiak, L. A. Khawli, and A. L. Epstein Construction and Preclinical Characterization of Fc-mGITRL for the Immunotherapy of Cancer Clin. Cancer Res., January 15, 2008; 14(2): 579 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Li, N. Perez, S. Karumuthil-Melethil, B. S. Prabhakar, M. J. Holterman, and C. Vasu Enhanced Engagement of CTLA-4 Induces Antigen-Specific CD4+CD25+Foxp3+ and CD4+CD25 TGF-beta1+ Adaptive Regulatory T Cells J. Immunol., October 15, 2007; 179(8): 5191 - 5203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. Wang, P. Wang, J. D. Gray, and D. A. Horwitz 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 J. Immunol., February 15, 2007; 178(4): 2018 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Inoue and Y. Aramaki Suppression of Skin Lesions by Transdermal Application of CpG-Oligodeoxynucleotides in NC/Nga Mice, a Model of Human Atopic Dermatitis J. Immunol., January 1, 2007; 178(1): 584 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Menoret, L. M. Myers, S.-J. Lee, R. S. Mittler, R. J. Rossi, and A. T. Vella TGFbeta Protein Processing and Activity through TCR Triggering of Primary CD8+ T Regulatory Cells J. Immunol., November 1, 2006; 177(9): 6091 - 6097. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hillyer, B. Dao, P. Niemiec, S. Lee, M. Doidge, I. Bemben, T. Neyestani, and B. Woodward Elevated Bioactivity of the Tolerogenic Cytokines, Interleukin-10 and Transforming Growth Factor-{beta}, in the Blood of Acutely Malnourished Weanling Mice Experimental Biology and Medicine, September 1, 2006; 231(8): 1439 - 1447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Cheng, H.-W. Chen, J.-P. Tsai, Y.-P. Lee, Y.-C. Shih, C.-M. Chang, and C.-C. Ting Clonal restriction of the expansion of antigen-specific CD8+ memory T cells by transforming growth factor-{beta} J. Leukoc. Biol., May 1, 2006; 79(5): 1033 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Mayack and L. J. Berg Cutting Edge: An Alternative Pathway of CD4+ T Cell Differentiation Is Induced Following Activation in the Absence of {gamma}-Chain-Dependent Cytokine Signals J. Immunol., February 15, 2006; 176(4): 2059 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G.-J. Ooi, G. Galatowicz, H. M. A. Towler, S. L. Lightman, and V. L. Calder Multiplex Cytokine Detection versus ELISA for Aqueous Humor: IL-5, IL-10, and IFN{gamma} Profiles in Uveitis Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 272 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Endharti, M. Rifa' I, Z. Shi, Y. Fukuoka, Y. Nakahara, Y. Kawamoto, K. Takeda, K.-i. Isobe, and H. Suzuki Cutting Edge: CD8+CD122+ Regulatory T Cells Produce IL-10 to Suppress IFN-{gamma} Production and Proliferation of CD8+ T Cells J. Immunol., December 1, 2005; 175(11): 7093 - 7097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Skapenko, J. R. Kalden, P. E. Lipsky, and H. Schulze-Koops The IL-4 Receptor {alpha}-Chain-Binding Cytokines, IL-4 and IL-13, Induce Forkhead Box P3-Expressing CD25+CD4+ Regulatory T Cells from CD25-CD4+ Precursors J. Immunol., November 1, 2005; 175(9): 6107 - 6116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. O. Krutzik, M. B. Hale, and G. P. Nolan Characterization of the Murine Immunological Signaling Network with Phosphospecific Flow Cytometry J. Immunol., August 15, 2005; 175(4): 2366 - 2373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, Z. Xu, R. C. Fuhlbrigge, V. Pena-Cruz, J. Lieberman, and T. S. Kupper Vaccinia Virus Induces Strong Immunoregulatory Cytokine Production in Healthy Human Epidermal Keratinocytes: a Novel Strategy for Immune Evasion J. Virol., June 15, 2005; 79(12): 7363 - 7370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Abbott, G. H. Palmer, K. A. Kegerreis, P. F. Hetrick, C. J. Howard, J. C. Hope, and W. C. Brown Rapid and Long-Term Disappearance of CD4+ T Lymphocyte Responses Specific for Anaplasma Marginale Major Surface Protein-2 (MSP2) in MSP2 Vaccinates following Challenge with Live A. marginale J. Immunol., June 1, 2005; 174(11): 6702 - 6715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Gangi, C. Vasu, D. Cheatem, and B. S. Prabhakar IL-10-Producing CD4+CD25+ Regulatory T Cells Play a Critical Role in Granulocyte-Macrophage Colony-Stimulating Factor-Induced Suppression of Experimental Autoimmune Thyroiditis J. Immunol., June 1, 2005; 174(11): 7006 - 7013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Brusko, C. H. Wasserfall, A. Agarwal, M. H. Kapturczak, and M. A. Atkinson An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells J. Immunol., May 1, 2005; 174(9): 5181 - 5186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Kang and P. M. Allen Priming in the Presence of IL-10 Results in Direct Enhancement of CD8+ T Cell Primary Responses and Inhibition of Secondary Responses J. Immunol., May 1, 2005; 174(9): 5382 - 5389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bonnefoix, P. Bonnefoix, P. Perron, J.-Q. Mi, W. F. Ng, R. Lechler, J.-C. Bensa, J.-Y. Cahn, and D. Leroux Quantitating Effector and Regulatory T Lymphocytes in Immune Responses by Limiting Dilution Analysis Modeling J. Immunol., March 15, 2005; 174(6): 3421 - 3431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Alvaro, M. Lejeune, M. T. Salvado, R. Bosch, J. F. Garcia, J. Jaen, A. H. Banham, G. Roncador, C. Montalban, and M. A. Piris Outcome in Hodgkin's Lymphoma Can Be Predicted from the Presence of Accompanying Cytotoxic and Regulatory T Cells Clin. Cancer Res., February 15, 2005; 11(4): 1467 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kipnis, H. Avidan, R. R. Caspi, and M. Schwartz Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: A dialogue with microglia PNAS, October 5, 2004; 101(suppl_2): 14663 - 14669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Rouse and S. Suvas Regulatory Cells and Infectious Agents: Detentes Cordiale and Contraire J. Immunol., August 15, 2004; 173(4): 2211 - 2215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vasu, B. S. Prabhakar, and M. J. Holterman Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity J. Immunol., August 15, 2004; 173(4): 2866 - 2876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-B. Park, D.-J. Paik, E. Jang, S. Hong, and J. Youn Acquisition of anergic and suppressive activities in transforming growth factor-{beta}-costimulated CD4+CD25- T cells Int. Immunol., August 1, 2004; 16(8): 1203 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Carbonneil, H. Saidi, V. Donkova-Petrini, and L. Weiss Dendritic cells generated in the presence of interferon-{alpha} stimulate allogeneic CD4+ T-cell proliferation: modulation by autocrine IL-10, enhanced T-cell apoptosis and T regulatory type 1 cells Int. Immunol., July 1, 2004; 16(7): 1037 - 1052. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
