Memory CD4 T cells emerge from effector T-cell progenitors

A hallmark of adaptive immunity is the generation of memory T cells that confer long- lived, antigen- specific protection against repeat challenges by pathogens(1-5). Understanding the mechanisms by which memory T cells arise is important for rational vaccination strategies and improved therapeutic interventions for chronic infections and autoimmune disorders. The large clonal expansion of CD8 T cells in response to some infections has made the development of CD8 T- cell memory more amenable to study, giving rise to a model of memory cell differentiation in which a fraction of fully competent effector T cells transition into long-lived memory T cells(4,6,7). Delineation of CD4 T- cell memory development has proved more difficult as a result of limitations on tracking the smaller populations of CD4 effector T cells generated during a pathogenic challenge(8-10), complicating efforts to determine whether CD4 memory T cells are direct descendants of effector T cells or whether they develop by alternative pathways(3,4). Here, using two complementary cytokine reporter mouse models to identify interferon ( IFN)- gamma-positive effector T cells and track their fate, we show that the lineage relationship between effector and memory CD4 T cells resembles that for CD8 T cells responding to the same pathogen. We find that, in parallel with effector CD8 T cells, IFN-gamma-positive effector CD4 T cells give rise to long- lived memory T cells capable of anamnestic responses to antigenic rechallenge.