The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells

Antigen-specific memory T cells are a critical component of protective immunity because of their increased frequency and enhanced reactivity after restimulation. However, it is unclear whether 'memory-like' T cells generated during lymphopenia-induced homeostatic proliferation can also offer protection against pathogens. Here we show that homeostatic proliferation–induced memory (HP-memory) CD8+ T cells controlled bacterial infection as effectively as 'true' memory CD8+ T cells, but their protective capacity required the presence of CD4+ T cells during homeostatic proliferation. The necessity for CD4 help was overcome, however, if the HP-memory CD8+ T cells lacked expression of TRAIL (tumor necrosis factor–related apoptosis-inducing ligand; also called Apo-2L). Thus, like conventional CD8+ memory T cells, the protective function of HP-memory CD8+ T cells shows dependence on CD4+ T cell help.