CD8⁺CD122⁺CD49d^low regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity

Abstract

The Fas/FasL (CD95/CD178) system is required for immune regulation; however, it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. We found that CD8+CD122+ cells, which are mostly composed of memory T cells in comparison with naïve cells in the CD8+CD122- population, were previously shown to include cells with regulatory activity and could be separated into CD49dlow cells and CD49dhigh cells. We established in vitro and in vivo experimental systems to evaluate the regulatory activity of CD122+ cells. Regulatory activity was observed in CD8+CD122+CD49dlow but not in CD8+CD122+CD49dhigh cells, indicating that the regulatory cells in the CD8+CD122+ population could be narrowed down to CD49dlow cells. CD8+CD122- cells taken from lymphoproliferation (lpr) mice were resistant to regulation by normal CD122+ Tregs. CD122+ Tregs taken from generalized lymphoproliferative disease (gld) mice did not regulate wild-type CD8+CD122- cells, indicating that the regulation by CD122+ Tregs is Fas/FasL-dependent. CD122+ Tregs taken from IL-10-deficient mice could regulate CD8+CD122- cells as equally as wild-type CD122+ Tregs both in vitro and in vivo. MHC class I-missing T cells were not regulated by CD122+ Tregs in vitro. CD122+ Tregs also regulated CD4+ cells in a Fas/FasL-dependent manner in vitro. These results suggest an essential role of Fas/FasL as a terminal effector of the CD122+ Tregs that kill activated T cells to maintain immune homeostasis.