B 세포 발생에서 조절 T 세포의 역할과 조절 T 세포와 류마티스 활막세포간의 상호작용

Abstract

CD4+Foxp3+ regulatory (Treg) cells are crucial for maintaining T cell homeostasis, but their impact on B lymphopoietic homeostasis remains largely unknown. Here we examined whether the absence of Treg cells impinges on B lymphopoiesis in the bone marrow using scurfy (sf) mice in which Treg cells are deficient due to a loss-of-function mutation of Foxp3 gene. The bone marrow from sf mice contained fewer B-lineage cells at all stages, common lymphoid progenitors, and lymphoid-primed multipotent progenitors than the bone marrow from wild-type littermates. The sf bone marrow also exhibited developmental arrest at the stages of hematopoietic stem cells and pro-B cells. These phenotypes were fixed by Treg cells reconstitution, indicating they were due to Treg-deficiency not due to Foxp3 mutation in the bone marrow cells. The sf bone marrow cells differentiated to B cells as comparable to the wild-type bone marrow cells in both in vitro culture and mixed bone marrow chimeric mice, demonstrating factors extrinsic to B lineage progenitor cells causeed the abnormal B lymphopoiesis in sf mice. CD4+ T cells and proinflammatory cytokines enriched in the sf bone marrow, including IL-6, TNF-α, and GM-CSF, inhibited in vitro differentiation of LSK cells toward B-lineage cells, which was derepressed by addition of Treg cells. Thus, our data suggest that Treg cells have an important niche in the bone marrow to guard B-lineage progenitor cells against inflammatory milieu. Next, we extended our study to examine fuctional features of Treg cells in inflamed local tissue. The synovium of diarthrodial joints is a major inflamed tissue affected by rheumatoid arthritis. Fibroblast-like synoviocytes (FLS) colocalize with leukocyte infiltrates in rheumatoid synovia. Proinflammatory leukocytes are known to amplify inflammation by signaling to FLS, but crosstalk between FLS and Treg cells remains uncharacterized. To address this possibility, we cocultured FLS lines derived from arthritic mice with Treg cells. FLS that expressed the ligand for glucocorticoid-induced TNF receptor family-related gene (GITR) decreased expression of Foxp3 and GITR in Treg cells in a contact-dependent manner. This effect was abolished by blocking antibody to GITR. On the other hand, the Treg cells caused the FLS to increase IL-6 production. These results demonstrate that inflamed FLS license Treg cells to down-regulate Foxp3 expression via the GITRL/GITR interaction while the Treg cells induce the FLS to increase their production of IL-6. Our findings suggest that the interaction between FLS and Treg cells dampens the anti-inflammatory activity of Treg cells and amplifies the proinflammatory activity of FLS, thereby exacerbating inflammatory arthritis. Thus, the present study addressed how Treg cells contribute to the developmet of bone marrow hematopoietic cells and react with stromal cells of inflamed synovia. This study highlights importance of Treg cells in normal hematopoiesis and maintenance of anti-inflammatory states.