Akane Kazuyuki, Kojima Seiji, Mak Tak W, Shiku Hiroshi, Suzuki Haruhiko
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan;
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan;
Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):2460-5. doi: 10.1073/pnas.1525098113. Epub 2016 Feb 11.
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.
Fas/FasL（CD95/CD178）系统对于免疫调节是必需的；然而，Fas/FasL分子在免疫系统中的哪些细胞、何时以及何处发挥作用尚不清楚。我们发现，与CD8(+)CD122(-)群体中的幼稚细胞相比，主要由记忆T细胞组成的CD8(+)CD122(+)细胞先前已被证明包含具有调节活性的细胞，并且可以分为CD49d(low)细胞和CD49d(high)细胞。我们建立了体外和体内实验系统来评估CD122(+)细胞的调节活性。在CD8(+)CD122(+)CD49d(low)细胞中观察到调节活性，而在CD8(+)CD122(+)CD49d(high)细胞中未观察到，这表明CD8(+)CD122(+)群体中的调节细胞可以缩小到CD49d(low)细胞。从淋巴细胞增殖（lpr）小鼠中获取的CD8(+)CD122(-)细胞对正常CD122(+)调节性T细胞的调节具有抗性。从全身性淋巴细胞增殖性疾病（gld）小鼠中获取的CD122(+)调节性T细胞不能调节野生型CD8(+)CD122(-)细胞，这表明CD122(+)调节性T细胞的调节是Fas/FasL依赖性的。从白细胞介素-10缺陷小鼠中获取的CD122(+)调节性T细胞在体外和体内均能与野生型CD122(+)调节性T细胞一样有效地调节CD8(+)CD122(-)细胞。MHC I类缺失的T细胞在体外不受CD122(+)调节性T细胞的调节。CD122(+)调节性T细胞在体外也以Fas/FasL依赖性方式调节CD4(+)细胞。这些结果表明Fas/FasL作为CD122(+)调节性T细胞的终末效应分子，通过杀伤活化的T细胞来维持免疫稳态具有重要作用。
