Suppression of allograft rejection by CD8+CD122+PD-1+ Tregs is dictated by their Fas ligand-initiated killing of effector T cells versus Fas-mediated own apoptosis

Oncotarget. 2017 Apr 11;8(15):24187-24195. doi: 10.18632/oncotarget.15551.

Abstract

Mounting evidence has shown that naturally occurring CD8+CD122+ T cells are regulatory T cells (Tregs) that suppress both autoimmunity and alloimmunity. We have previously shown that CD8+CD122+PD-1+ Tregs not only suppress allograft rejection, but also are more potent in suppression than conventional CD4+CD25+ Tregs. However, the mechanisms underlying their suppression of alloimmunity are not well understood. In an adoptive T-cell transfer model of mice lacking lymphocytes, we found that suppression of skin allograft rejection by CD8+CD122+PD-1+ Tregs was mostly dependent on their expression of Fas ligand as either lacking Fas ligand or blocking it with antibodies largely abolished their suppression of allograft rejection mediated by transferred T cells. Their suppression was also mostly reversed when effector T cells lacked Fas receptor. Indeed, these FasL+ Tregs induced T cell apoptosis in vitro in a Fas/FasL-dependent manner. However, their suppression of T cell proliferation in vitro was dependent on IL-10, but not FasL expression. Furthermore, adoptive transfer of CD8+CD122+PD-1+ Tregs significantly extended allograft survival even in wild-type mice if Tregs lacked Fas receptor or if recipients received recombinant IL-15, as these two measures synergistically expanded adoptively-transferred Tregs in recipients. Thus, this study may have important implications for Treg therapies in clinical transplantation.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; T cell apoptosis; Treg; immunoregulation; transplantation.

MeSH terms

  • Allografts
  • Animals
  • Apoptosis* / immunology
  • Biomarkers
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytotoxicity, Immunologic
  • Fas Ligand Protein / metabolism*
  • Graft Rejection / immunology*
  • Immunomodulation
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • fas Receptor / metabolism*

Substances

  • Biomarkers
  • Fas Ligand Protein
  • Interleukin-2 Receptor beta Subunit
  • Programmed Cell Death 1 Receptor
  • fas Receptor