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

Abstract

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.

Abstract

CD4 ⁺ T cells contain a T-bet ^high memory-phenotype (MP) population with innate-like functions. Here the authors characterize the requirements for their differentiation at homeostasis and identify a function for IL-12 that is tonically produced by type 1 dendritic cells in an MyD88- and CD40-dependent, but foreign PAMP-independent manner.