| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104
To study the cis- and trans-acting factors that mediate programmed death 1 (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.
This article has been cited by other articles:
|
|
 |
|
  K. Izawa, J. Kitaura, Y. Yamanishi, T. Matsuoka, A. Kaitani, M. Sugiuchi, M. Takahashi, A. Maehara, Y. Enomoto, T. Oki, et al. An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcR{gamma} in Mast Cells J. Immunol., July 15, 2009; 183(2): 925 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Petrovas, B. Chaon, D. R. Ambrozak, D. A. Price, J. J. Melenhorst, B. J. Hill, C. Geldmacher, J. P. Casazza, P. K. Chattopadhyay, M. Roederer, et al. Differential Association of Programmed Death-1 and CD57 with Ex Vivo Survival of CD8+ T Cells in HIV Infection J. Immunol., July 15, 2009; 183(2): 1120 - 1132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Crawford and E. J. Wherry Editorial: Therapeutic potential of targeting BTLA J. Leukoc. Biol., July 1, 2009; 86(1): 5 - 8. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yao, S. Wang, Y. Zhu, L. Luo, G. Zhu, S. Flies, H. Xu, W. Ruff, M. Broadwater, I.-H. Choi, et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection Blood, June 4, 2009; 113(23): 5811 - 5818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wong, Y. Liu, J. Yip, R. Chand, J. L. Wee, L. Oates, B. Nieswandt, A. Reheman, H. Ni, N. Beauchemin, et al. CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo Blood, February 19, 2009; 113(8): 1818 - 1828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Kinter, E. J. Godbout, J. P. McNally, I. Sereti, G. A. Roby, M. A. O'Shea, and A. S. Fauci The Common {gamma}-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands J. Immunol., November 15, 2008; 181(10): 6738 - 6746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Fourmentraux-Neves, A. Jalil, S. Da Rocha, C. Pichon, S. Chouaib, G. Bismuth, and A. Caignard Two opposite signaling outputs are driven by the KIR2DL1 receptor in human CD4+ T cells Blood, September 15, 2008; 112(6): 2381 - 2389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Freeman Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek PNAS, July 29, 2008; 105(30): 10275 - 10276. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-J. Wang, F.-C. Chou, C.-H. Chu, J.-C. Wu, S.-H. Lin, D.-M. Chang, and H.-K. Sytwu Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice: The Paradox in Transgenic Models Diabetes, July 1, 2008; 57(7): 1861 - 1869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. W. Lee, M. A. Ostrowski, and S. D. Gray-Owen CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation J. Immunol., May 15, 2008; 180(10): 6827 - 6835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Palmer, D. G. Mack, A. K. Martin, M. Gillespie, M. M. Mroz, L. A. Maier, and A. P. Fontenot Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease J. Immunol., February 15, 2008; 180(4): 2704 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Posevitz, B. Arndt, T. Krieger, N. Warnecke, B. Schraven, and L. Simeoni Regulation of T Cell Homeostasis by the Transmembrane Adaptor Protein SIT J. Immunol., February 1, 2008; 180(3): 1634 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Chung, I. Dougherty, P. D. Cruz Jr., and K. Ariizumi Syndecan-4 Mediates the Coinhibitory Function of DC-HIL on T Cell Activation J. Immunol., November 1, 2007; 179(9): 5778 - 5784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Chemnitz, D. Eggle, J. Driesen, S. Classen, J. L. Riley, S. Debey-Pascher, M. Beyer, A. Popov, T. Zander, and J. L. Schultze RNA fingerprints provide direct evidence for the inhibitory role of TGF{beta} and PD-1 on CD4+ T cells in Hodgkin lymphoma Blood, November 1, 2007; 110(9): 3226 - 3233. [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]
|
|
|
|
|
|
Y. Liu, M. J. Kruhlak, J.-J. Hao, and S. Shaw Rapid T cell receptor-mediated SHP-1 S591 phosphorylation regulates SHP-1 cellular localization and phosphatase activity J. Leukoc. Biol., September 1, 2007; 82(3): 742 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Terawaki, Y. Tanaka, T. Nagakura, T. Hayashi, S. Shibayama, K. Muroi, T. Okazaki, B. Mikami, D. N. Garboczi, T. Honjo, et al. Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function Int. Immunol., July 2, 2007; (2007) dxm059v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Tsushima, S. Yao, T. Shin, A. Flies, S. Flies, H. Xu, K. Tamada, D. M. Pardoll, and L. Chen Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy Blood, July 1, 2007; 110(1): 180 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Classen, T. Zander, D. Eggle, J. M. Chemnitz, B. Brors, I. Buchmann, A. Popov, M. Beyer, R. Eils, S. Debey, et al. Human Resting CD4+ T Cells Are Constitutively Inhibited by TGFbeta under Steady-State Conditions J. Immunol., June 1, 2007; 178(11): 6931 - 6940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Zhang, Z. Zhang, X. Wang, J.-L. Fu, J. Yao, Y. Jiao, L. Chen, H. Zhang, J. Wei, L. Jin, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors Blood, June 1, 2007; 109(11): 4671 - 4678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Tessmer, C. Fugere, F. Stevenaert, O. V. Naidenko, H. J. Chong, G. Leclercq, and L. Brossay KLRG1 binds cadherins and preferentially associates with SHIP-1 Int. Immunol., April 1, 2007; 19(4): 391 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Radziewicz, C. C. Ibegbu, M. L. Fernandez, K. A. Workowski, K. Obideen, M. Wehbi, H. L. Hanson, J. P. Steinberg, D. Masopust, E. J. Wherry, et al. Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression J. Virol., March 15, 2007; 81(6): 2545 - 2553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. von Bergwelt-Baildon, A. Popov, T. Saric, J. Chemnitz, S. Classen, M. S. Stoffel, F. Fiore, U. Roth, M. Beyer, S. Debey, et al. CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition Blood, July 1, 2006; 108(1): 228 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Chemnitz, A. R. Lanfranco, I. Braunstein, and J. L. Riley B and T Lymphocyte Attenuator-Mediated Signal Transduction Provides a Potent Inhibitory Signal to Primary Human CD4 T Cells That Can Be Initiated by Multiple Phosphotyrosine Motifs. J. Immunol., June 1, 2006; 176(11): 6603 - 6614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Fortin, A. Larbi, O. Lesur, N. Douziech, and T. Fulop Jr. Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions J. Leukoc. Biol., May 1, 2006; 79(5): 1061 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Boettler, E. Panther, B. Bengsch, N. Nazarova, H. C. Spangenberg, H. E. Blum, and R. Thimme Expression of the Interleukin-7 Receptor Alpha Chain (CD127) on Virus-Specific CD8+ T Cells Identifies Functionally and Phenotypically Defined Memory T Cells during Acute Resolving Hepatitis B Virus Infection. J. Virol., April 1, 2006; 80(7): 3532 - 3540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhu, I. Guleria, A. Khosroshahi, T. Chitnis, J. Imitola, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury Differential Role of Programmed Death-Ligand 1 and Programmed Death-Ligand 2 in Regulating the Susceptibility and Chronic Progression of Experimental Autoimmune Encephalomyelitis J. Immunol., March 15, 2006; 176(6): 3480 - 3489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Raimondi, W. J. Shufesky, D. Tokita, A. E. Morelli, and A. W. Thomson Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells. J. Immunol., March 1, 2006; 176(5): 2808 - 2816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Chemnitz, J. Driesen, S. Classen, J. L. Riley, S. Debey, M. Beyer, A. Popov, T. Zander, and J. L. Schultze Prostaglandin E2 Impairs CD4+ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma Cancer Res., January 15, 2006; 66(2): 1114 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Keir, Y. E. Latchman, G. J. Freeman, and A. H. Sharpe Programmed Death-1 (PD-1):PD-Ligand 1 Interactions Inhibit TCR-Mediated Positive Selection of Thymocytes J. Immunol., December 1, 2005; 175(11): 7372 - 7379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Salmond, G. Huyer, A. Kotsoni, L. Clements, and D. R. Alexander The src Homology 2 Domain-Containing Tyrosine Phosphatase 2 Regulates Primary T-Dependent Immune Responses and Th Cell Differentiation J. Immunol., November 15, 2005; 175(10): 6498 - 6508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. V. Parry, J. M. Chemnitz, K. A. Frauwirth, A. R. Lanfranco, I. Braunstein, S. V. Kobayashi, P. S. Linsley, C. B. Thompson, and J. L. Riley CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms Mol. Cell. Biol., November 1, 2005; 25(21): 9543 - 9553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hirano, K. Kaneko, H. Tamura, H. Dong, S. Wang, M. Ichikawa, C. Rietz, D. B. Flies, J. S. Lau, G. Zhu, et al. Blockade of B7-H1 and PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity Cancer Res., February 1, 2005; 65(3): 1089 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Riley and C. H. June The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation Blood, January 1, 2005; 105(1): 13 - 21. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
