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 CD49d(low) cells and CD49d(high) 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(+)CD49d(low) but not in CD8(+)CD122(+)CD49d(high) cells, indicating that the regulatory cells in the CD8(+)CD122(+) population could be narrowed down to CD49d(low) 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.
Highlights
The Fas/FasL (CD95/CD178) system is required for immune regulation; it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system
Our study demonstrated that CD8+CD122+CD49dlow regulatory T cells induced apoptosis in target T cells depending on death receptor Fas (CD95)–FasL (CD178) interaction
These results indicate that CD8+CD122− cells reduce their number by some effect of CD8+CD122+ cells, and such an effect is much stronger in CD49dlow cells than in CD49dhigh cells
Summary
The Fas/FasL (CD95/CD178) system is required for immune regulation; it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. CD122+ Tregs 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. Because Fas-mutant (lpr) and FasL-deficient (gld) mice show lymphoproliferative changes, it has been suggested that the Fas/FasL system is important for suppression/regulation of activated effector T cells [7, 8]. No reliable reports suggesting that CD8+ T cells use the Fas/FasL system for their regulatory action are available It is not clear precisely which subset of T cells express FasL or where Fas/FasL-dependent CD8+ Tregs, if such cells exist, are located and at which point they function. The ultimate pathophysiological role of the Fas/FasL system is still unknown
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