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Journal of Virology, May 2007, p. 4766-4775, Vol. 81, No. 9
0022-538X/07/$08.00+0     doi:10.1128/JVI.02608-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Primary CD4⁺ T-Cell Responses Provide both Helper and Cytotoxic Functions during Epstein-Barr Virus Infection and Transformation of Fetal Cord Blood B Cells

Georgina J. MacArthur,^1, A. Douglas Wilson,³ Martin A. Birchall,² and Andrew J. Morgan^1*

Department of Cellular and Molecular Medicine, School of Medical Sciences,¹ Clinical Sciences at South Bristol,² Division of Veterinary Pathology, Infection and Immunity, University of Bristol, Bristol, United Kingdom³

Received 27 November 2006/ Accepted 9 February 2007

Most humans carry Epstein-Barr virus (EBV) in circulating memory B cells as a latent infection that is controlled by an immune response. When infected by EBV, B lymphocytes in fetal cord blood are readily transformed to lymphoblastoid cell lines (LCL). It is frequently assumed that this high efficiency of transformation is due to the absence of a primary immune response. However, cord blood lymphocytes stimulated with autologous LCL yield CD4⁺ T cells that can completely inhibit the growth of LCL by a major histocompatibility complex-restricted cytotoxic mechanism mediated by granulysin and granzyme B. Because EBV-transformed B cells maintain the phenotype of antigen-activated B-cell blasts, they can potentially receive inhibitory or helper functions from CD4⁺ T cells. To assess these functions, the effect of EBV-specific CD4⁺ T cells on the efficiency of virus transformation of autologous B cells was assayed. Paradoxically, although the cytotoxic CD4⁺ T-cell lines reduced EBV B-cell transformation at a high effector/target ratio of 10:1, they caused a twofold increase in B-cell transformation at the lower effector/target ratio of 1:1. Th1-polarized CD4⁺ T cells were more effective at inhibiting B-cell transformation, but Th2-polarized cell lines had reduced cytotoxic activity, were unable to inhibit LCL growth, and caused a 10-fold increase in transformation efficiency. Tonsil lymphoid follicles lacked NK cells and CD8⁺ T cells but contained CD4⁺ T cells. We propose that CD4⁺ T cells provide helper or cytotoxic functions to EBV-transformed B cells and that the balance of these functions within tonsil compartments is critical in establishing asymptomatic primary EBV infection and maintaining a stable lifelong latent infection.

Published ahead of print on 21 February 2007.

Present address: Department of Virology, Faculty of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom.