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The CD8+ T cell response to Epstein-Barr virus (EBV) is well characterized. Much less is known about the evolution of the CD4+ T cell response. Here we show that EBV stimulates a primary burst of effector CD4+ T cells and this is followed by a period of down-regulation. A small population of EBV-specific effector CD4+ T cells survives during the lifelong persistent phase of infection. The EBV-specific effector CD4+ T cells accumulate within a CD27+ CD28+ differentiation compartment during primary infection and remain enriched within this compartment throughout the persistent phase of infection. Analysis of CD4+ T cell responses to individual epitopes from EBV latent and lytic cycle proteins confirms the observation that the majority of the effector cells express both CD27 and CD28, although CD4+ T cells specific for lytic cycle antigens have a greater tendency to express CD45RA than those specific for the latent antigens. In clear contrast, effector CD4+ T cells specific for cytomegalovirus (CMV) accumulate within the CD27- CD28+ and CD27- CD28- compartments. There are striking parallels in terms of the differentiation of CD8+ T cells specific for EBV and CMV. The results challenge current ideas on the definition of memory subsets.

Original publication




Journal article


J Exp Med

Publication Date





903 - 911


CD28 Antigens, CD4-Positive T-Lymphocytes, Cell Differentiation, Cytomegalovirus, Epitopes, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Humans, Immunologic Memory, Leukocyte Common Antigens, Lymphocyte Activation, Phenotype, T-Lymphocyte Subsets, Tumor Necrosis Factor Receptor Superfamily, Member 7, Viral Proteins