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Induction of rapid T cell death and phagocytic activity by Fas-deficient lpr macrophages.

ABSTRACT: Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas-Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-?/IFN-?R. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-?B activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression.

SUBMITTER: Oura R

PROVIDER: S-EPMC3539689 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Induction of rapid T cell death and phagocytic activity by Fas-deficient lpr macrophages.

Oura Ritsuko R Arakaki Rieko R Yamada Akiko A Kudo Yasusei Y Tanaka Eiji E Hayashi Yoshio Y Ishimaru Naozumi N

Journal of immunology (Baltimore, Md. : 1950) 20121219 2

Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas-Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was p ...[more]

PMID: 23255359

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Project description:Previous studies showed that loss of tumor necrosis factor ? (TNF?) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNF? induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNF? alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Fas(lpr) /J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Fas(lpr) /J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Fas(lpr) /J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Fas(lpr) /J mice had elevated Treg cells in both spleens and bones of B6.MRL/Fas(lpr) /J but decreased percentage of activated T cells in bone tissues. Fracture led to ?30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Fas(lpr) /J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Fas(lpr) /J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNF? signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption.

Dataset Information

Induction of rapid T cell death and phagocytic activity by Fas-deficient lpr macrophages.

Publications

Induction of rapid T cell death and phagocytic activity by Fas-deficient lpr macrophages.

Similar Datasets

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