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

Nat Commun. 2020 Jul 6;11(1):3366. 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-bethigh, T-betlow, and T-bet- subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh 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-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • Cell Communication / immunology
  • Cell Differentiation / immunology*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Homeostasis / immunology*
  • Immunologic Memory / immunology*
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Signal Transduction / immunology
  • T-Box Domain Proteins / immunology*
  • T-Box Domain Proteins / metabolism
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism


  • CD40 Antigens
  • CD8 Antigens
  • CD8alpha antigen
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • CD40 Ligand
  • Interleukin-12