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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1408-1416.
Prepublished online as a Blood First Edition Paper on October 16, 2003; DOI 10.1182/blood-2003-03-0930.
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IMMUNOBIOLOGY
Direct killing of Epstein-Barr virus (EBV)–infected B cells by CD4 T cells directed against the EBV lytic protein BHRF1
Elise Landais,
Xavier Saulquin,
Emmanuel Scotet,
Lydie Trautmann,
Marie-Alix Peyrat,
John L. Yates,
William W. Kwok,
Marc Bonneville, and
Elisabeth Houssaint
From the INSERM U463, Institut de Biologie, Nantes, France; Faculté des Sciences de Nantes, Nantes, France; Virginia Mason Research Center, Seattle, WA; and Roswell Park Center Institute, Buffalo, NY.
Due to their low frequency, CD4 T-cell responses to Epstein-Barr virus (EBV) lytic antigens are, so far, poorly characterized. Human peptide major histocompatibility complex (MHC) class II multimers provide a means to detect and characterize such rare T cells. Along a screening of T-cell responses to lytic or latent EBV antigens within peripheral blood leukocyte (PBL)– or synovial-derived CD4 T-cell lines, we identified an human leukocyte antigen–DR*0401 (HLA-DR*0401)–restricted epitope derived from BHRF1 (BamHI fragment H rightward open reading frame 1), a viral protein produced during the early stages of the lytic cycle. We show here that T-cell responses to this particular BHRF1 epitope are shared by most EBV-infected DR*0401+ individuals, as BHRF1-specific CD4 T cells could be sorted out from all the DRB*0401 T-cell lines analyzed, using magnetic beads coated with recombinant BHRF1/DR*0401 complexes. Sorting with these peptide MHC class II multimers was very efficient, as the yield of recovery of BHRF1-specific T cells was nearly 100%. Functional analysis of a large number of clones responding to BHRF1/DR*0401 demonstrated their cytolytic action against autologous and allogeneic DR*0401+ EBV-transformed B-lymphoblastoid cell lines (B-LCLs), with 40% to 80% killing efficiency and potent interferon  production, thus suggesting that this CD4 T-cell population contributes to the control of EBV replication. B-LCL lysis by these T-cell clones was DR*0401 dependent, EBV dependent, and was not merely due to bystander killing. Taken together, these data provide the first demonstration that a lytic antigen can induce a direct cytolytic response against EBV-infected cells.
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