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

• Published in: Nature communications 2020-07, Vol.11 (1), p.3366-3366, Article 3366
• Main Authors: Kawabe, Takeshi, Yi, Jaeu, Kawajiri, Akihisa, Hilligan, Kerry, Fang, Difeng, Ishii, Naoto, Yamane, Hidehiro, Zhu, Jinfang, Jankovic, Dragana, Kim, Kwang Soon, Trinchieri, Giorgio, Sher, Alan
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 14/19; 631/250/1619/554/1898; 631/250/2152/1566/1571; 631/250/2504; 631/250/254; 64/60; Antigens; CD4 antigen; CD40 antigen; CD40L protein; Cell differentiation; Dendritic cells; Differentiation; Effector cells; Genotype & phenotype; Homeostasis; Humanities and Social Sciences; Immunological memory; Interleukin 12; Lymphocytes; Lymphocytes T; Memory cells; multidisciplinary; MyD88 protein; Phenotypes; Science; Science (multidisciplinary); Self-recognition; Subpopulations
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17136-1

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. 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.