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Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection.

ABSTRACT: Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor-specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody-mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN-?) versus the contact-dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune-deficient C57BL/6 rag-/- ?c-/- recipients, who also received monoclonal anti-major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild-type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN-?-deficient NK cells or host IFN-? neutralization led to amelioration of these lesions. Use of either perforin-deficient NK cells or CD95 (Fas)-deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell-derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN-? production and contact-dependent cytotoxic activity are rate-limiting effector pathways that contribute to this form of antibody-induced chronic allograft vasculopathy.

SUBMITTER: Lin CM

PROVIDER: S-EPMC5083186 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other

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Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection.

Lin C M CM Plenter R J RJ Coulombe M M Gill R G RG

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20160707 11

Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor-specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody-mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytoki ...[more]

PMID: 27163757

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Project description:Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-?) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator ?-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-? production. ?-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and ?-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, ?-galactosylceramide (?-GalCer) using a mouse model. Pharmacologic targeting of ?-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-? responses. By contrast, within several hours of ?-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired ?-GalCer-induced IFN-? responses, independent of ?-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/?-catenin signaling that curbs IFN-? responses, but that, subsequently, Wnt ligands sustain IFN-? expression independent of ?-catenin activity. Our analyses in ICG001-treated mice confirmed a role for ?-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to ?-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and ?-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of ?-catenin to NKT cell functions.

Dataset Information

Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection.

Publications

Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection.

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