Low-affinity T cells are programmed to maintain normal primary responses but are impaired in their recall to...

T cell responses to low-affinity T cell receptor (TCR) ligands occur in the context of infection, tumors, and autoimmunity despite diminished TCR signal strength. The processes that enable such responses remain unclear. We show that distinct mechanisms drive effector/memory development in high- and low-affinity T cells. Low-affinity cells preferentially differentiate into memory precursors of a central memory phenotype that are interleukin (IL)-12R(lo), IL-7R(hi), and Eomes(hi). Strikingly, in contrast to naive cells, low-affinity memory cells were impaired in the response to low- but not high-affinity ligands, indicating that low-affinity cells are programmed to generate diverse immune responses while avoiding autoreactivity. Affinity and antigen dose directly correlated with IL-12R signal input and T-bet but not with Eomes expression because low- affinity signals were more potent inducers of Eomes at a high antigen dose. Our studies explain how weak antigenic signals induce complete primary immune responses and provide a framework for therapeutic intervention.