CD4+ T cells are composed of naïve, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells. Naïve and pathogen-specific memory cells play key roles in adaptive immunity while the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. In this work we show that MP cells are autonomously generated from peripheral naïve cells in the absence of infectious stimulation in a TCR- and CD28-dependent manner. We further demonstrate that MP cells contain a T-bethi subpopulation and that this subpopulation requires tonic IL-12 derived from CD8α+ (type 1) dendritic cells for its generation. Importantly, these cells rapidly produce IFN-γ in response to IL-12 in the absence of pathogen recognition and provide antigen-nonspecific host resistance against Toxoplasma gondii and Mycobacterium tuberculosis infection that drives Th1-type immunity while enhancing the adaptive CD4+ T cell responses. Together, these findings reveal that T-bethi MP CD4+ T cells are spontaneously generated from naïve precursors by IL-12 and possess a novel innate-like effector function by which they produce an early, cytokine-driven protective response against Th1-inducing pathogens.
This work was supported by the Intramural Research Program of the NIAID, NIH.