| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115; and
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115
Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.
This article has been cited by other articles:
|
|
 |
|
  M. Hayashi, T. Kouki, N. Takasu, S. Sunagawa, and I. Komiya Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients. Eur. J. Endocrinol., June 1, 2008; 158(6): 817 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lafon, F. Megret, S. G. Meuth, O. Simon, M. L. Velandia Romero, M. Lafage, L. Chen, L. Alexopoulou, R. A. Flavell, C. Prehaud, et al. Detrimental Contribution of the Immuno-Inhibitor B7-H1 to Rabies Virus Encephalitis J. Immunol., June 1, 2008; 180(11): 7506 - 7515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Gong, R. Zhang, J. Zhang, L. Xu, F. Zhang, W. Xu, Y. Wang, Y. Chu, and S. Xiong {alpha}-Dystroglycan is involved in positive selection of thymocytes by participating in immunological synapse formation FASEB J, May 1, 2008; 22(5): 1426 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-X. Hubert, S. A. Kinkel, K. E. Webster, P. Cannon, P. E. Crewther, A. I. Proeitto, L. Wu, W. R. Heath, and H. S. Scott A Specific Anti-Aire Antibody Reveals Aire Expression Is Restricted to Medullary Thymic Epithelial Cells and Not Expressed in Periphery J. Immunol., March 15, 2008; 180(6): 3824 - 3832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lazar-Molnar, A. Gacser, G. J. Freeman, S. C. Almo, S. G. Nathenson, and J. D. Nosanchuk The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum PNAS, February 19, 2008; 105(7): 2658 - 2663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. I. Albu, D. Feng, D. Bhattacharya, N. A. Jenkins, N. G. Copeland, P. Liu, and D. Avram BCL11B is required for positive selection and survival of double-positive thymocytes J. Exp. Med., November 26, 2007; 204(12): 3003 - 3015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Wong, R. R. Scotland, R. L. Lau, C. Wang, A. J. Korman, W. M. Kast, and J. S. Weber Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs Int. Immunol., October 1, 2007; 19(10): 1223 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. G. Kasler and E. Verdin Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes Mol. Cell. Biol., July 15, 2007; 27(14): 5184 - 5200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Baldwin and K. A. Hogquist Transcriptional Analysis of Clonal Deletion In Vivo J. Immunol., July 15, 2007; 179(2): 837 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Watson, A. J. T. George, and D. F. P. Larkin Differential effects of costimulatory pathway modulation on corneal allograft survival. Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3417 - 3422. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
