The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8⁺ T cells

A functional memory T cell pool is critical for resistance to pathogen reinfection. Lymphopenia produces memory-like CD8⁺ T cells through homeostatic proliferation, and such "HP-memory" cells can control lethal bacterial infections similarly to conventional, antigen-experienced, memory T cells. These 2 pathways for memory T cell generation are quite distinct. We show here, however, that similar factors are required for production of protective memory CD8 T cells via both homeostatic and conventional pathways. Induction of protective HP-memory CD8 T cells requires CD4⁺ T cell "help," which we show is antigen nonspecific yet requires CD40L-CD40 interactions with host cells. The functional competence of HP-memory CD8 T cells also requires release of endogenous bacterial components (which follows irradiation-induced lymphopenia), potentially mimicking the role of adjuvants in conventional immune responses. Lymphopenic environments lacking these key factors support similar CD8 T cell homeostatic proliferation and the acquisition of memory phenotype, yet the HP-memory cells generated are defective in pathogen elimination. These findings suggest unexpected parallels in the requirements for generating protective memory CD8 T cells by distinct pathways, and they suggest ways to bolster immune competence during recovery from lymphopenia.