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B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.

ABSTRACT: B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic ? cells, we used a CD8 T cell-mediated diabetes model (AI4??) in which CD8 T cells recognize an endogenous self-Ag, and found that mice lacking B7x developed more severe diabetes than control AI4?? mice. Conversely, mice overexpressing B7x in the ? cells (Rip-B7xAI4??) were diabetes free. Furthermore, adoptive transfer of effector AI4?? CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4?? mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4?? mice. Although AI4?? CD8 T cells in Rip-B7xAI4?? and AI4?? mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4?? mice than in RIP-B7xAI4?? mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells, and that local overexpression of B7x on pancreatic ? cells is sufficient to abolish CD8 T cell-induced diabetes.

SUBMITTER: Lee JS

PROVIDER: S-EPMC3466330 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.

Lee Jun Sik JS Scandiuzzi Lisa L Ray Anjana A Wei Joyce J Hofmeyer Kimberly A KA Abadi Yael M YM Loke P'ng P Lin Juan J Yuan Jianda J Serreze David V DV Allison James P JP Zang Xingxing X

Journal of immunology (Baltimore, Md. : 1950) 20120912 8

B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic β cells, we used a CD8 T ...[more]

PMID: 22972920

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Project description:Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis. The Mito DNADX assay, which allows for the accurate real-time quantification of mtDNA damage in a 96-well platform, was performed in parallel. We confirmed that EB-42168 selectively inhibits LRRK2 phosphorylation on G2019S LRRK2 relative to wild-type LRRK2. On the other hand, MLi-2 was equipotent for wild-type and G2019S LRRK2. Acute treatment with EB-42168 inhibited LRRK2 phosphorylation and also restored mtDNA damage to healthy control levels. We further investigated the relationship between LRRK2 kinase activity, mtDNA damage and mitophagy. Levels of mtDNA damage caused by G2019S LRRK2 were fully re-established within 2 h of a LRRK2 inhibitor wash out and recovery experiment, indicating the mtDNA damage phenotype is highly dynamic. G2019S LRRK2 mitophagy defects were not alleviated with LRRK2 kinase inhibition, suggesting that mitophagy is not mechanistically regulating LRRK2 kinase-mediated reversal of mtDNA damage in this acute timeframe. Abrogation of mtDNA damage with the mutant selective tool inhibitor EB-42168 demonstrates the potential of a precision medicine approach for LRRK2 G2019S PD. Levels of mtDNA damage may serve as a potential pharmacodynamic biomarker of altered kinase activity that could be useful for small molecule development and clinical trials.

Dataset Information

B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.

Publications

B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.

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