Memory-phenotype CD4 T cells spontaneously generated under steady-state conditions exert innate T1-like effector function.

Conventional CD4 T cells are composed of naïve, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells under steady state. Naïve and pathogen-specific memory cells play key roles in adaptive immunity, whereas the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. We show that MP cells are autonomously generated from peripheral naïve cells in the absence of infectious stimulation in a T cell receptor (TCR)- and CD28-dependent manner. We further demonstrate that MP cells contain a T-bet subpopulation that is continuously generated by environmental interleukin-12 (IL-12) and rapidly produces interferon-γ (IFN-γ) in response to IL-12 in the absence of pathogen recognition. These cells can provide nonspecific host resistance against infection while enhancing the adaptive CD4 T cell responses. Together, these findings reveal that MP cells are continuously generated from naïve precursors and have a previously undescribed innate immune function by which they produce an early, T helper cell type 1 (T1)-like protective response against pathogens.