Naturally arising memory-phenotype CD4+ T lymphocytes contain an undifferentiated population that can generate TH1, TH17, and Treg cells

Sci Adv. 2024 Dec 6;10(49):eadq6618. doi: 10.1126/sciadv.adq6618. Epub 2024 Dec 4.

Abstract

Memory-phenotype (MP) CD4+ T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (TH1)/17-like subsets, functional significance of the T-bet- Rorγt- subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into TH1/17/regulatory T (Treg) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, TH1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only TH1/17-differentiated subsets but a polyclonal, transcriptomically immature "undifferentiated" subpopulation at homeostasis. Furthermore, our data argue that while the T-bet+ Rorγt- MP subset is terminally TH1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into TH1/17/Treg cells, with the latter response tonically constrained by preexisting Treg cells. Together, our results identify undifferentiated MP CD4+ T lymphocytes as a unique precursor that has a diverse differentiation potential to generate TH1/17/Treg cells to contribute to pathogenesis of inflammation.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • Cell Differentiation*
  • Immunologic Memory
  • Memory T Cells / immunology
  • Memory T Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Phenotype
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism
  • Th1 Cells* / immunology
  • Th1 Cells* / metabolism
  • Th17 Cells* / immunology
  • Th17 Cells* / metabolism

Substances

  • Nuclear Receptor Subfamily 1, Group F, Member 3