The importance of CD8 1 CD122 1 Treg in the maintenance of immune homeostasis has been previously demonstrated in mice. Because the expression pattern of CD8 and CD122 in humans is different from that in mice, human CD8 1 Treg that correspond to the murine CD8 1 CD122 1 Treg have not been identified. In this study, we performed DNA microarray analyses to compare the gene expression profiles of CD8 1 CD122 1 cells and CD8 1 CD122 À cells in mice and found that CXCR3 was preferentially expressed in CD8 1 CD122 1 cells. When we analyzed the expression of CD122 and CXCR3 in murine CD8 1 cells, we observed a definite population of CD122 1 CXCR3 1 cells. CD8 1 CXCR3 1 cells in mice showed similar regulatory activities to CD8 1 CD122 1 cells by in vivo and in vitro assays. While CD8 1 CD122 1 CXCR3 1 cells are present in mice, CD8 1 CXCR3 1 cells, but not CD8 1 CD122 1 cells, are present in humans. In the in vitro assay, human CD8 1 CXCR3 1 cells showed the regulatory activity of producing IL-10 and suppressing IFN-c production from CD8 1 CXCR3 À cells. These results suggest that human CD8 1 CXCR3 1 T cells are the counterparts of murine CD8 1 CD122 1 Treg.Key words: CD8 cells . Cytokine receptors . Human . Treg IntroductionMaintenance of immune homeostasis is of paramount importance. The immune system, which fights pathogenic microorganisms invading the body, also can damage the host organism, i.e. autoimmune diseases and allergies. Thus, the immune reaction must be strictly regulated by multiple mechanisms, including professional regulatory cells. Such professional regulatory cells are mostly included in T cells that are thought to be ''the control tower'' of the immune system. There may be no doubt that an extraordinary progression of the research of Treg in this decade has been led by the discovery of CD4 1 CD25 1 naturally arising Treg [1][2][3][4]. Because T cells respond to some specific antigen, it is no wonder that one may dream of antigen-specific Treg that strictly suppress some specific immune response but do not affect other immune responses, and such an idea has also pushed the research of Treg. Mature T cells are generally divided into two populations by their cell-surface markers, CD4 1 and CD8 1 , and normal immune response is achieved by a good balance of CD4 1 and CD8 1 cells. Although Treg are also thought to distribute in both CD4 1 and CD8 1 populations, the research of Treg is skewed towards those in CD4 1 population.We originally identified CD8 1 CD122 1 Treg and proved their importance in the maintenance of immune homeostasis in vivo [5]. CD8 1 CD122 1 Treg are categorized into Treg of naturally arising type. One benefit to handle Treg of naturally arising type is that they enable us to do prospective investigation and to expect application of these cells for the treatment of immunebased disorders. For instance, we may be able to collect naturally arising Treg that are promised to become functional regulatory cells from patients suffering from immune-based intractable disease, expand them in so...

In the thymus, low-affinity T cell antigen receptor (TCR) engagement facilitates positive selection of a useful T cell repertoire. Here we report that TCR responsiveness of mature CD8+ T cells is fine-tuned by their affinity for positively selecting peptides in the thymus and that optimal TCR responsiveness requires positive selection on MHC class I-associated peptides produced by the thymoproteasome, which is specifically expressed in the thymic cortical epithelium. Thymoproteasome-independent positive selection of monoclonal CD8+ T cells results in aberrant TCR responsiveness, homeostatic maintenance, and immune responses to infection. These results demonstrate a novel aspect of positive selection, in which TCR affinity for positively selecting peptides produced by thymic epithelium determines the subsequent antigen responsiveness of mature CD8+ T cells in the periphery.

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.

Lack of CD4(+)CD25(+)FOXP3(+) Tregs before treatment may predict resistance to IVIg therapy in patients with KD.

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