Characterization of the CD4⁺ T Cell Response to Epstein-Barr Virus during Primary and Persistent Infection

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.