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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2280-2289. Prepublished online as a Blood First Edition Paper on June 6, 2006; DOI 10.1182/blood-2006-04-015164. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-04-015164v1 108/7/2280    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gandhi, M. K. Articles by Khanna, R. Search for Related Content PubMed PubMed Citation Articles by Gandhi, M. K. Articles by Khanna, R. Related Collections Immunobiology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen–specific CD8+ T-cell function in Hodgkin lymphoma patients Maher K. Gandhi, Eleanore Lambley, Jaikumar Duraiswamy, Ujjwal Dua, Corey Smith, Suzanne Elliott, Devinder Gill, Paula Marlton, John Seymour, and Rajiv Khanna From the Tumor Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane; Haematology Service, Peter MacCallum Cancer Centre, University of Melbourne; and Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia. In Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg (HRS) cells constitute only 0.5% of 10% of the diseased tissue. The surrounding cellular infiltrate is enriched with T cells that are hypothesized to modulate antitumor immunity. We show that a marker of regulatory T cells, LAG-3, is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T cells (CD4+ CD25hi CD45 ROhi, CD4+ CTLA4hi, and CD4+ LAG-3hi) were elevated in HL patients with active disease when compared with remission. Longitudinal profiling of EBV-specific CD8+ T-cell responses in 94 HL patients revealed a selective loss of interferon- expression by CD8+ T cells specific for latent membrane proteins 1 and 2 (LMP1/2), irrespective of EBV tissue status. Intratumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 nor EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor-infiltrating lymphocytes was coincident with impairment of LMP1/2-specific T-cell function. In vitro pre-exposure of peripheral blood mononuclear cells to HRS cell line supernatant significantly increased the expansion of regulatory T cells and suppressed LMP-specific T-cell responses. Deletion of CD4+ LAG-3+ T cells enhanced LMP-specific reactivity. These findings indicate a pivotal role for regulatory T cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. R.N. Baumforth, A. Birgersdotter, G. M. Reynolds, W. Wei, G. Kapatai, J. R. Flavell, E. Kalk, K. Piper, S. Lee, L. Machado, et al. Expression of the Epstein-Barr Virus-Encoded Epstein-Barr Virus Nuclear Antigen 1 in Hodgkin's Lymphoma Cells Mediates Up-Regulation of CCL20 and the Migration of Regulatory T Cells Am. J. Pathol., July 1, 2008; 173(1): 195 - 204. [Abstract] [Full Text] [PDF] S. Mittal, N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma Blood, June 1, 2008; 111(11): 5359 - 5370. [Abstract] [Full Text] [PDF] C. Casati, C. Camisaschi, L. Novellino, A. Mazzocchi, F. Triebel, L. Rivoltini, G. Parmiani, and C. Castelli Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation J. Immunol., March 15, 2008; 180(6): 3782 - 3788. [Abstract] [Full Text] [PDF] R. Yamamoto, M. Nishikori, T. Kitawaki, T. Sakai, M. Hishizawa, M. Tashima, T. Kondo, K. Ohmori, M. Kurata, T. Hayashi, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma Blood, March 15, 2008; 111(6): 3220 - 3224. [Abstract] [Full Text] [PDF] P. E. Zarek, C.-T. Huang, E. R. Lutz, J. Kowalski, M. R. Horton, J. Linden, C. G. Drake, and J. D. Powell A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells Blood, January 1, 2008; 111(1): 251 - 259. [Abstract] [Full Text] [PDF] G Kapatai and P Murray Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma J. Clin. Pathol., December 1, 2007; 60(12): 1342 - 1349. [Abstract] [Full Text] [PDF] C. Brignone, C. Grygar, M. Marcu, K. Schakel, and F. Triebel A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells J. Immunol., September 15, 2007; 179(6): 4202 - 4211. [Abstract] [Full Text] [PDF] M. K. Gandhi, G. Moll, C. Smith, U. Dua, E. Lambley, O. Ramuz, D. Gill, P. Marlton, J. F. Seymour, and R. Khanna Galectin-1 mediated suppression of Epstein-Barr virus specific T-cell immunity in classic Hodgkin lymphoma Blood, August 15, 2007; 110(4): 1326 - 1329. [Abstract] [Full Text] [PDF] P. Juszczynski, J. Ouyang, S. Monti, S. J. Rodig, K. Takeyama, J. Abramson, W. Chen, J. L. Kutok, G. A. Rabinovich, and M. A. Shipp The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma PNAS, August 7, 2007; 104(32): 13134 - 13139. [Abstract] [Full Text] [PDF] R. F. Ambinder Epstein-Barr Virus and Hodgkin Lymphoma Hematology, January 1, 2007; 2007(1): 204 - 209. [Abstract] [Full Text] [PDF]

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