| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,¶
* Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
Guanghua Rheumatology Hospital, Shanghai, China;
Department of Immunology, M. D. Anderson Cancer Center, Houston, TX 77030;
Departments of Neurology and Immunology, Baylor College of Medicine, Houston, TX 77030; and
¶ E-Institutes of Shanghai Universities, Shanghai, China
T cell activation and function are critically regulated by positive and negative costimulatory molecules. Aberrant expression and function of costimulatory molecules have been associated with persistent activation of self-reactive T cells in autoimmune diseases such as rheumatoid arthritis (RA). In this study, initial analysis of costimulatory molecules led to the unexpected observation that, in addition to CD80, several negative regulators (e.g., CTLA-4, programmed death-1 (PD-1), and PD ligand-1) were overexpressed in synovial T cells and macrophages derived from RA patients as opposed to controls. The expression of CD80 and PD ligand-1 on monocytes could be induced in vitro by IFN-
and TNF-
that were produced abundantly in RA-derived synovial fluid (SF). Furthermore, the soluble form of negative costimulatory molecules occurred at high concentrations in sera and SF of RA patients and correlated with titers of rheumatoid factor in RA patients. In particular, the levels of soluble PD-1 were found to correlate significantly with those of TNF- in SF derived from RA patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant (PD-1
ex3) and could functionally block the regulatory effect of membrane-bound PD-1 on T cell activation. Our data indicate a novel pathogenic pathway in which overexpression of negative costimulatory molecules to restrict synovial inflammation in RA is overruled by the excessive production of soluble costimulatory molecules.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The work was supported by grants from the National Natural Science Foundation of China (NSFC-30430650 and NSFC-30571731), Shanghai Commission of Science and Technology (04JC14040, 04DZ14902, and PJ200500330), Shanghai Municipal Health Bureau (LJ06046), and Shanghai Leading Academic Discipline Project (T206) and the Doctoral Program Fund of Ministry of Education of China (No. 20050266005). C.D. is an Arthritis Investigator of the Arthritis Foundation and is supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
2 Address correspondence and reprint requests to: Jingwu Zhang, Baylor College of Medicine, Mail Station NB302, One Baylor Plaza, Houston, TX 77030. E-mail address: jzang{at}bcm.tmc.edu
3 Abbreviations used in this paper: PD-1, programmed death-1; PD-L1, programmed death-ligand 1; OA, osteoarthritis; RA, rheumatoid arthritis; SF, synovial fluid; SFMC, SF mononuclear cells; flPD-1, full-length PD-1; PD-1ex3, PD-1 delete exon 3; PD1ex2, PD-1 delete exon 2; PD-1ex2,3, PD-1 delete exon 2,3; CT, cycle threshold; sPD-1, soluble PD-1.
This article has been cited by other articles:
|
|
 |
|
  M Her, D Kim, M Oh, H Jeong, and I Choi Increased expression of soluble inducible costimulator ligand (ICOSL) in patients with systemic lupus erythematosus Lupus, May 1, 2009; 18(6): 501 - 507. [Abstract] [PDF]
|
|
|
|
 |
|
 Z. Xu, M. A. Hurchla, H. Deng, O. Uluckan, F. Bu, A. Berdy, M. C. Eagleton, E. A. Heller, D. H. Floyd, W. P. Dirksen, et al. Interferon-{gamma} Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases J. Biol. Chem., February 13, 2009; 284(7): 4658 - 4666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Taglauer, A. S. Trikhacheva, J. G. Slusser, and M. G. Petroff Expression and Function of PDCD1 at the Human Maternal-Fetal Interface Biol Reprod, September 1, 2008; 79(3): 562 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ren, L. Lu, T. B. Guo, J. Qiu, Y. Yang, A. Liu, and J. Z. Zhang Novel Immunomodulatory Properties of Berbamine through Selective Down-Regulation of STAT4 and Action of IFN-{gamma} in Experimental Autoimmune Encephalomyelitis J. Immunol., July 15, 2008; 181(2): 1491 - 1498. [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]
|
|
|
|
 |
|
 T. Okazaki and T. Honjo PD-1 and PD-1 ligands: from discovery to clinical application Int. Immunol., July 2, 2007; (2007) dxm057v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Nielsen, T. Barington, S. Hansen, and S. T. Lillevang Comment on "Aberrant Regulation of Synovial T Cell Activation by Soluble Costimulatory Molecules in Rheumatoid Arthritis" J. Immunol., April 15, 2007; 178(8): 4708 - 4708. [Full Text] [PDF]
|
|
|
|
|
|
B. Wan, H. Nie, A. Liu, and J. Z. Zhang Response to Comment on "Aberrant Regulation of Synovial T Cell Activation by Soluble Costimulatory Molecules in Rheumatoid Arthritis" J. Immunol., April 15, 2007; 178(8): 4709 - 4709. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
