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Adenovirus-Specific CD4⁺ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction¹

Bianca Heemskerk^2,*, Tamara van Vreeswijk^*, Louise A. Veltrop-Duits^*, Claudia C. Sombroek^*, Kees Franken, Renate M. Verhoosel, Pieter S. Hiemstra, Daphne van Leeuwen, Maaike E. Ressing, René E. M. Toes^¶, Maarten J. D. van Tol^* and Marco W. Schilham^3,*

^* Department of Pediatrics, Department of Immunohematology and Bloodtransfusion, Department of Pulmonology, Department of Medical Microbiology, and ^¶ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

Human adenovirus (HAdV) infection is a frequent and potentially severe complication following allogeneic stem cell transplantation in children. Because treatment with antiviral drugs is often ineffective, adoptive transfer of donor-derived HAdV-specific T cells able to control viral replication of HAdV of multiple serotypes may be an option for therapy. In healthy donors, predominantly HAdV-specific T cells expressing CD4 are detected. In this study, a preclinical in vitro model was used to measure the antiviral effect of HAdV-specific CD4⁺ T cells. CD4⁺ HAdV-specific T cell clones restricted by HLA class II molecules were generated and most of these clones recognized conserved peptides derived from the hexon protein. These cross-reactive T cell clones were able to control viral replication of multiple serotypes of HAdV in EBV-transformed B cells (B-LCL), melanoma cells (MJS) and primary bronchial epithelial cells through cognate interaction. The HAdV-specific CD4⁺ T cell clones were able to specifically lyse infected target cells using a perforin-dependent mechanism. Antigenic peptides were also presented to the CD4⁺ T cell clones when derived from endogenously produced hexon protein. Together, these results show that cross-reactive HAdV-specific CD4⁺ T cells can control replication of HAdV in vitro and provide a rationale for the use of HAdV-specific T cells in adoptive immunotherapy protocols for control of life-threatening HAdV-infections in immunocompromised patients.

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 This work was supported by Dutch Cancer Foundation Grant RUL-2001-2492 and European Community Grant QLK2-CT-2002-01432.

² Current address: Surgery Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1201.

³ Address correspondence and reprint requests to Dr. Marco W. Schilham, Department of Pediatrics, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: M.W.Schilham{at}lumc.nl

⁴ Abbreviations used in this paper: HAdV, human adenovirus; SCT, stem cell transplant; PBEC, primary bronchial epithelial cell; MB, methylene blue; eGFP, enhanced GFP; MOI, multiplicity of infection; TCID₅₀, tissue culture-infective dose of 50%; CRA, chromium release assay; CMA, concanamycin A.

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