CD8 T Cell Cross-Reactivity Networks Mediate Heterologous Immunity in Human EBV and Murine Vaccinia Virus Infections

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Abstract
In this study, we demonstrate complex networks of CD8 T cell cross-reactivities between influenza A virus and EBV in humans and between lymphocytic choriomeningitis virus and vaccinia virus in mice. We also show directly that cross-reactive T cells mediate protective heterologous immunity in mice. Subsets of T cell populations reactive with one epitope cross-reacted with either of several other epitopes encoded by the same or the heterologous virus. Human T cells specific to EBV-encoded BMLF1280–288 could be cross-reactive with two influenza A virus or two other EBV epitopes. Mouse T cells specific to the vaccinia virus-encoded a11r198–205 could be cross-reactive with three different lymphocytic choriomeningitis virus, one Pichinde virus, or one other vaccinia virus epitope. Patterns of cross-reactivity differed among individuals, reflecting the private specificities of the host’s immune repertoire and divergence in the abilities of T cell populations to mediate protective immunity. Defining such cross-reactive networks between commonly encountered human pathogens may facilitate the design of vaccines.