| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Producing Regulatory T Cells from CD4+CD25- Precursors1
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
Previously we reported that TGF-
has an important role in the
generation and expansion of human "professional"
CD4+CD25+ regulatory T cells in the periphery
that have a cytokine-independent mechanism of action. In this study we
used low-dose staphylococcal enterotoxin to induce T cell-dependent Ab
production. We report that TGF- induces activated
CD4+CD25- T cells to become Th3 suppressor
cells. While stimulating CD4+ cells with TGF- modestly
increased expression of CD25 and intracellular CTLA-4 in primary
cultures, upon secondary stimulation without TGF- the total number
and those expressing these markers dramatically increased. This
expansion was due to both increased proliferation and protection of
these cells from activation-induced apoptosis. Moreover, adding as few
as 1% of these TGF--primed CD4+ T cells to fresh
CD4+ cells and B cells markedly suppressed IgG production.
The inhibitory effect was mediated by TGF- and was also partially
contact dependent. Increased TGF- production was associated with a
decreased production of IFN-
and IL-10. Depletion studies revealed
that the precursors of these TGF--producing CD4+
suppressor cells were CD25 negative. These studies provide evidence
that CD4+CD25+ regulatory cells in human blood
consist of at least two subsets that have TGF--dependent and
independent mechanisms of action. TGF- has an essential role in the
generation of both of these T suppressor cell subsets from peripheral T
cells. The ability to induce CD4+ and CD8+
cells to become regulatory cells ex vivo has the potential to be useful
in the treatment of autoimmune diseases and to prevent transplant
rejection.
This article has been cited by other articles:
|
|
 |
|
  M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. Bommhardt Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation J. Immunol., November 15, 2009; 183(10): 6124 - 6134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Howie, K. F. Nolan, S. Daley, E. Butterfield, E. Adams, H. Garcia-Rueda, C. Thompson, N. J. Saunders, S. P. Cobbold, Y. Tone, et al. MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation J. Immunol., October 1, 2009; 183(7): 4197 - 4204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xie, M. Wu, R. Song, J. Ma, Y. Shi, W. Qin, and Y. Jin A glucocorticoid amplifies IL-2-induced selective expansion of CD4+CD25+FOXP3+ regulatory T cells in vivo and suppresses graft-versus-host disease after allogeneic lymphocyte transplantation Acta Biochim Biophys Sin, September 1, 2009; 41(9): 781 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Noel, C. Brinster, G. Semana, and D. Bruniquel Modulation of the TCR stimulation strength can render human activated CD4+ T cells suppressive Int. Immunol., September 1, 2009; 21(9): 1025 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Han, Q. Guo, M. Zhang, Z. Chen, and X. Cao CD69+CD4+CD25- T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-{beta}1 J. Immunol., January 1, 2009; 182(1): 111 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Chen, X. Liang, A. J. Peterson, D. H. Munn, and B. R. Blazar The Indoleamine 2,3-Dioxygenase Pathway Is Essential for Human Plasmacytoid Dendritic Cell-Induced Adaptive T Regulatory Cell Generation J. Immunol., October 15, 2008; 181(8): 5396 - 5404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Tonkin, J. He, G. Barbour, and K. Haskins Regulatory T Cells Prevent Transfer of Type 1 Diabetes in NOD Mice Only When Their Antigen Is Present In Vivo J. Immunol., October 1, 2008; 181(7): 4516 - 4522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhao, S. Yu, D. C. Fitzgerald, M. Elbehi, B. Ciric, A. M. Rostami, and G.-X. Zhang IL-12R{beta}2 Promotes the Development of CD4+CD25+ Regulatory T Cells J. Immunol., September 15, 2008; 181(6): 3870 - 3876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. B. Marshall, W. R. Vorachek, L. B. Steppan, D. V. Mourich, and N. I. Kerkvliet Functional Characterization and Gene Expression Analysis of CD4+CD25+ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin J. Immunol., August 15, 2008; 181(4): 2382 - 2391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. Wang, and D. A. Horwitz Cutting Edge: Foxp3+CD4+CD25+ Regulatory T Cells Induced by IL-2 and TGF-{beta} Are Resistant to Th17 Conversion by IL-6 J. Immunol., June 1, 2008; 180(11): 7112 - 7116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Elrefaei, C. A. R. Baker, N. G. Jones, D. R. Bangsberg, and H. Cao Presence of Suppressor HIV-Specific CD8+ T Cells Is Associated with Increased PD-1 Expression on Effector CD8+ T Cells J. Immunol., June 1, 2008; 180(11): 7757 - 7763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Perez, S. Karumuthil-Melethil, R. Li, B. S. Prabhakar, M. J. Holterman, and C. Vasu Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-{beta}1+-Adaptive Regulatory T Cell Generation J. Immunol., May 15, 2008; 180(10): 6566 - 6576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. A. Taher, B. C. A. M. van Esch, G. A. Hofman, P. A. J. Henricks, and A. J. M. van Oosterhout 1{alpha},25-Dihydroxyvitamin D3 Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-{beta} J. Immunol., April 15, 2008; 180(8): 5211 - 5221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Razmara, B. Hilliard, A. K. Ziarani, Y. H. Chen, and M. L. Tykocinski CTLA-4{middle dot}Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells Int. Immunol., April 1, 2008; 20(4): 471 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Sumpter, K. K. Payne, and D. S. Wilkes Regulation of the NFAT pathway discriminates CD4+CD25+ regulatory T cells from CD4+CD25- helper T cells J. Leukoc. Biol., March 1, 2008; 83(3): 708 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Selvaraj and T. L. Geiger Mitigation of Experimental Allergic Encephalomyelitis by TGF-{beta} Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance J. Immunol., March 1, 2008; 180(5): 2830 - 2838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Niedbala, B. Cai, H. Liu, N. Pitman, L. Chang, and F. Y. Liew Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40 PNAS, September 25, 2007; 104(39): 15478 - 15483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Kapp, K. Honjo, L. M. Kapp, K. Goldsmith, and R. P. Bucy Antigen, in the Presence of TGF-beta, Induces Up-Regulation of FoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses J. Immunol., August 15, 2007; 179(4): 2105 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Selvaraj and T. L. Geiger A Kinetic and Dynamic Analysis of Foxp3 Induced in T Cells by TGF-beta J. Immunol., June 15, 2007; 178(12): 7667 - 7677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Couper, D. G. Blount, J. B. de Souza, I. Suffia, Y. Belkaid, and E. M. Riley Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice J. Immunol., April 1, 2007; 178(7): 4136 - 4146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Stein-Streilein and A. W. Taylor An eye's view of T regulatory cells J. Leukoc. Biol., March 1, 2007; 81(3): 593 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Liu, L. Y. Wong, T. Jang, A. H. Shah, I. Park, X. Yang, Q. Zhang, S. Lonning, B. A. Teicher, and C. Lee Tumor Evasion of the Immune System by Converting CD4+CD25- T Cells into CD4+CD25+ T Regulatory Cells: Role of Tumor-Derived TGF-beta J. Immunol., March 1, 2007; 178(5): 2883 - 2892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Elrefaei, F. L. Ventura, C. A. R. Baker, R. Clark, D. R. Bangsberg, and H. Cao HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells J. Immunol., March 1, 2007; 178(5): 3265 - 3271. [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]
|
|
|
|
 |
|
 S. Nadkarni, C. Mauri, and M. R. Ehrenstein Anti-TNF-{alpha} therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-{beta} J. Exp. Med., January 22, 2007; 204(1): 33 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Seo, S. U. Lee, Y. H. Park, W. C. Davis, L. K. Fox, and G. A. Bohach Long-Term Staphylococcal Enterotoxin C1 Exposure Induces Soluble Factor-Mediated Immunosuppression by Bovine CD4+ and CD8+ T Cells Infect. Immun., January 1, 2007; 75(1): 260 - 269. [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. E. Weber, J. Harbertson, E. Godebu, G. A. Mros, R. C. Padrick, B. D. Carson, S. F. Ziegler, and L. M. Bradley Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo. J. Immunol., April 15, 2006; 176(8): 4730 - 4739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, W. Stohl, K. S. Kim, J. D. Gray, and D. A. Horwitz TGF-beta Requires CTLA-4 Early after T Cell Activation to Induce FoxP3 and Generate Adaptive CD4+CD25+ Regulatory Cells J. Immunol., March 15, 2006; 176(6): 3321 - 3329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, L. Meng, J. H. Wang, M. Watanabe, M. L. Barr, D. V. Cramer, J. D. Gray, and D. A. Horwitz Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient Int. Immunol., February 1, 2006; 18(2): 279 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sugita, T. F. Ng, P. J. Lucas, R. E. Gress, and J. W. Streilein B7+ Iris Pigment Epithelium Induce CD8+ T Regulatory Cells; Both Suppress CTLA-4+ T Cells J. Immunol., January 1, 2006; 176(1): 118 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shimizu, R. Iida, Y. Sato, E. Moriizumi, A. Nishikawa, and Y. Ishida Cross-Linking of CD45 on Suppressive/Regulatory T Cells Leads to the Abrogation of Their Suppressive Activity In Vitro J. Immunol., April 1, 2005; 174(7): 4090 - 4097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-K. Kang, M. A. Michaels, B. R. Berner, and S. K. Datta Very Low-Dose Tolerance with Nucleosomal Peptides Controls Lupus and Induces Potent Regulatory T Cell Subsets J. Immunol., March 15, 2005; 174(6): 3247 - 3255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Walker, B. D. Carson, G. T. Nepom, S. F. Ziegler, and J. H. Buckner De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells PNAS, March 15, 2005; 102(11): 4103 - 4108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cong, A. Konrad, N. Iqbal, R. D. Hatton, C. T. Weaver, and C. O. Elson Generation of Antigen-Specific, Foxp3-Expressing CD4+ Regulatory T Cells by Inhibition of APC Proteosome Function J. Immunol., March 1, 2005; 174(5): 2787 - 2795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Rao, A. L. Petrone, and P. D. Ponath Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-{beta} J. Immunol., February 1, 2005; 174(3): 1446 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Gunnlaugsdottir, S. M. Maggadottir, and B. R. Ludviksson Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-{beta}1 on CD4+ and CD8+ naive human T-cells Int. Immunol., January 1, 2005; 17(1): 35 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. E. Anderson, J. M. McNiff, C. Matte, I. Athanasiadis, W. D. Shlomchik, and M. J. Shlomchik Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease Blood, September 1, 2004; 104(5): 1565 - 1573. [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]
|
|
|
|
|
|
S. M. Wahl, J. Swisher, N. McCartney-Francis, and W. Chen TGF-{beta}: the perpetrator of immune suppression by regulatory T cells and suicidal T cells J. Leukoc. Biol., July 1, 2004; 76(1): 15 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Sumpter and D. S. Wilkes Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1129 - L1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, J. D. Gray, H. Soucier, and D. A. Horwitz Natural and Induced CD4+CD25+ Cells Educate CD4+CD25- Cells to Develop Suppressive Activity: The Role of IL-2, TGF-{beta}, and IL-10 J. Immunol., May 1, 2004; 172(9): 5213 - 5221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, M. N. Koss, F. Quismorio Jr., J. D. Gray, and D. A. Horwitz CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-{beta} Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome J. Immunol., February 1, 2004; 172(3): 1531 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cosmi, F. Liotta, E. Lazzeri, M. Francalanci, R. Angeli, B. Mazzinghi, V. Santarlasci, R. Manetti, V. Vanini, P. Romagnani, et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes Blood, December 1, 2003; 102(12): 4107 - 4114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Vigouroux, E. Yvon, H.-J. Wagner, E. Biagi, G. Dotti, U. Sili, C. Lira, C. M. Rooney, and M. K. Brenner Induction of Antigen-Specific Regulatory T Cells following Overexpression of a Notch Ligand by Human B Lymphocytes J. Virol., October 15, 2003; 77(20): 10872 - 10880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Horwitz, S. G. Zheng, and J. D. Gray 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 J. Leukoc. Biol., October 1, 2003; 74(4): 471 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mizobuchi, K. Yasufuku, Y. Zheng, M. A. Haque, K. M. Heidler, K. Woods, G. N. Smith Jr., O. W. Cummings, T. Fujisawa, J. S. Blum, et al. Differential Expression of Smad7 Transcripts Identifies the CD4+CD45RChigh Regulatory T Cells That Mediate Type V Collagen-Induced Tolerance to Lung Allografts J. Immunol., August 1, 2003; 171(3): 1140 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-m. Chen, M. J. O'Shaughnessy, I. Gramaglia, A. Panoskaltsis-Mortari, W. J. Murphy, S. Narula, M. G. Roncarolo, and B. R. Blazar IL-10 and TGF-{beta} induce alloreactive CD4+CD25- T cells to acquire regulatory cell function Blood, June 15, 2003; 101(12): 5076 - 5083. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
