Requirements for the differentiation of innate T-bet^high memory-phenotype CD4⁺ T lymphocytes under steady state

CD4⁺ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4⁺ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bet^high, T-bet^low, and T-bet⁻ subsets, with innate, Th1-like effector activity exclusively associated with T-bet^high cells. We further show that the latter population depends on IL-12 produced by CD8α⁺ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4⁺ T lymphocytes. We propose that optimal differentiation of T-bet^high MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.