|
|
Blood, 1 October 2007, Vol. 110, No. 7, pp. 2501-2510.
Prepublished online as a Blood First Edition Paper on June 15, 2007; DOI 10.1182/blood-2007-01-070748.
Previous Article | Table of Contents | Next Article 
IMMUNOBIOLOGY
OX40 costimulation turns off Foxp3+ Tregs
Minh Diem Vu1,
Xiang Xiao1,
Wenda Gao1,
Nicolas Degauque1,
Ming Chen1,
Alexander Kroemer1,
Nigel Killeen2,
Naoto Ishii3, and
Xian Chang Li1
1 Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA;
2 Department of Microbiology and Immunology, University of California San Francisco;
3 Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
OX40 is a recently identified T-cell costimulatory molecule that belongs to the TNF/TNFR superfamily. OX40 can be expressed by both activated T effector cells and Foxp3+ Tregs. It is well known that OX40 delivers a potent costimulatory signal to T effector cells, but very little is known about the role of OX40 in regulating the suppressor properties of Foxp3+ Tregs and the de novo generation of new inducible Foxp3+ Tregs from T effector cells. In the present study, we found, by using a newly created foxp3gfp knockin model, that OX40 was dispensable for the genesis and suppressor functions of naturally arising CD4+Foxp3+ Tregs, but stimulating OX40 on the Foxp3+ Tregs abrogated their ability to suppress T effector cell proliferation, IFN- production, and T effector cell-mediated allograft rejection. OX40 costimulation did not significantly affect proliferation and survival of the naturally arising Foxp3+ Tregs, but profoundly inhibited Foxp3 gene expression. Importantly, OX40 costimulation to T effector cells prevented the induction of new inducible Foxp3+ Tregs from T effector cells. Our study identified OX40 as a key negative regulator of Foxp3+ Tregs and may have important clinical implications in models of transplantation and autoimmunity.

CiteULike Connotea Del.icio.us Digg Reddit Technorati What's this?
Related Article in Blood Online:
-
OX40 costimulation and regulatory T cells
- Jerzy W. Kupiec-Weglinski
Blood 2007 110: 2217-2218.
[Full Text]
[PDF]
This article has been cited by other articles:

|
 |

|
 |
 
C. E. Ruby, M. A. Yates, D. Hirschhorn-Cymerman, P. Chlebeck, J. D. Wolchok, A. N. Houghton, H. Offner, and A. D. Weinberg
Cutting Edge: OX40 Agonists Can Drive Regulatory T Cell Expansion if the Cytokine Milieu Is Right
J. Immunol.,
October 15, 2009;
183(8):
4853 - 4857.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Houot, M. J. Goldstein, H. E. Kohrt, J. H. Myklebust, A. A. Alizadeh, J. T. Lin, J. M. Irish, J. A. Torchia, A. Kolstad, L. Chen, et al.
Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion
Blood,
October 15, 2009;
114(16):
3431 - 3438.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Piconese, G. Gri, C. Tripodo, S. Musio, A. Gorzanelli, B. Frossi, R. Pedotti, C. E. Pucillo, and M. P. Colombo
Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation
Blood,
September 24, 2009;
114(13):
2639 - 2648.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Kuczma, R. Podolsky, N. Garge, D. Daniely, R. Pacholczyk, L. Ignatowicz, and P. Kraj
Foxp3-Deficient Regulatory T Cells Do Not Revert into Conventional Effector CD4+ T Cells but Constitute a Unique Cell Subset
J. Immunol.,
September 15, 2009;
183(6):
3731 - 3741.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. Hirschhorn-Cymerman, G. A. Rizzuto, T. Merghoub, A. D. Cohen, F. Avogadri, A. M. Lesokhin, A. D. Weinberg, J. D. Wolchok, and A. N. Houghton
OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis
J. Exp. Med.,
May 11, 2009;
206(5):
1103 - 1116.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Houot and R. Levy
T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy
Blood,
April 9, 2009;
113(15):
3546 - 3552.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Krause, M. Bruckner, C. Uermosi, E. Singer, M. Groettrup, and D. F. Legler
Prostaglandin E2 enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells
Blood,
March 12, 2009;
113(11):
2451 - 2460.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. E. Ruby and A. D. Weinberg
OX40-Enhanced Tumor Rejection and Effector T Cell Differentiation Decreases with Age
J. Immunol.,
February 1, 2009;
182(3):
1481 - 1489.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. Wilde, S. Dolff, X. Cai, C. Specker, J. Becker, M. Totsch, U. Costabel, J. Durig, A. Kribben, J. W. C. Tervaert, et al.
CD4+CD25+ T-cell populations expressing CD134 and GITR are associated with disease activity in patients with Wegener's granulomatosis
Nephrol. Dial. Transplant.,
January 1, 2009;
24(1):
161 - 171.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. E. Burrell, G. Lu, X. C. Li, and D. K. Bishop
OX40 Costimulation Prevents Allograft Acceptance Induced by CD40-CD40L Blockade
J. Immunol.,
January 1, 2009;
182(1):
379 - 390.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W. Duan, T. So, and M. Croft
Antagonism of Airway Tolerance by Endotoxin/Lipopolysaccharide through Promoting OX40L and Suppressing Antigen-Specific Foxp3+ T Regulatory Cells
J. Immunol.,
December 15, 2008;
181(12):
8650 - 8659.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Abe, S. Ueha, J. Suzuki, Y. Tokano, K. Matsushima, and S. Ishikawa
Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus
Am. J. Pathol.,
December 1, 2008;
173(6):
1682 - 1692.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. L. Hippen, P. Harker-Murray, S. B. Porter, S. C. Merkel, A. Londer, D. K. Taylor, M. Bina, A. Panoskaltsis-Mortari, P. Rubinstein, N. Van Rooijen, et al.
Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells
Blood,
October 1, 2008;
112(7):
2847 - 2857.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Xiao, A. Kroemer, W. Gao, N. Ishii, G. Demirci, and X. C. Li
OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo
J. Immunol.,
September 1, 2008;
181(5):
3193 - 3201.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. N. Golovina, T. Mikheeva, M. M. Suhoski, N. A. Aqui, V. C. Tai, X. Shan, R. Liu, R. R. Balcarcel, N. Fisher, B. L. Levine, et al.
CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function
J. Immunol.,
August 15, 2008;
181(4):
2855 - 2868.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. J. Gough, C. E. Ruby, W. L. Redmond, B. Dhungel, A. Brown, and A. D. Weinberg
OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor
Cancer Res.,
July 1, 2008;
68(13):
5206 - 5215.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Joetham, S. Matsubara, M. Okamoto, K. Takeda, N. Miyahara, A. Dakhama, and E. W. Gelfand
Plasticity of Regulatory T Cells: Subversion of Suppressive Function and Conversion to Enhancement of Lung Allergic Responses
J. Immunol.,
June 1, 2008;
180(11):
7117 - 7124.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Piconese, B. Valzasina, and M. P. Colombo
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection
J. Exp. Med.,
April 14, 2008;
205(4):
825 - 839.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|