Human regulatory T cells control TCR signaling and susceptibility to suppression in CD4+ T cells

J Leukoc Biol. 2016 Jul;100(1):5-16. doi: 10.1189/jlb.2HI0815-334R. Epub 2015 Dec 29.

Abstract

Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells.

Keywords: Teff proliferation; Treg; cell surface markers.

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cytokines / metabolism
  • Humans
  • Immune Tolerance / immunology*
  • Immunosuppression Therapy*
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Cytokines
  • Receptors, Antigen, T-Cell