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Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance.

ABSTRACT: In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.

SUBMITTER: Papatriantafyllou M

PROVIDER: S-EPMC3277179 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance.

Papatriantafyllou Maria M Moldenhauer Gerhard G Ludwig Julia J Tafuri Anna A Garbi Natalio N Hollmann Gorana G Küblbeck Günter G Klevenz Alexandra A Schmitt Sabine S Pougialis Georg G Niehrs Christof C Gröne Hermann-Josef HJ Hämmerling Gunter J GJ Arnold Bernd B Oelert Thilo T

Proceedings of the National Academy of Sciences of the United States of America 20120117 5

In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following inte ...[more]

PMID: 22307622

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Project description:Interventions: Individuals with stage IV colorectal cancer who are planned to undergo surgery to remove their primary tumour +/- metastatic disease as part of their routine cancer care will be recruited to this study. At the time of surgery, once the specimen has been surgically resected, a number of fresh tissue samples will be obtained from the specimen for the research study. These samples will include lymph nodes, a small sample of the primary tumour, a sample of normal tissue, and a sample of a metastasis. These samples will be obtained by a senior colorectal surgeon under the supervision of pathology staff. In addition, a blood sample (up to 40ml) will be taken from the participant via their routinely inserted peripheral vein cannula once the participant is under general anaesthesia or at the appropriate time prior to surgery co-ordinated with diagnostic sampling by the anaesthetist. Samples obtained will be processed for single cell RNA sequencing analysis. Remaining tissue, cells and plasma that have been isolated from tissue and blood will be cryopreserved and stored in a secure manner. Participants will not be required to attend any follow up study visits for this study. The Peter MacCallum Cancer Centre hospital electronic medical record will be reviewed from time of initial diagnosis up to 3 years post-surgery for all participants who choose to enrol. Only relevant clinical data regarding the participant will be obtained and stored in a secure and de-identified manner. This will include basic demographics, diagnosis, stage and site of primary tumour, site(s) of metastatic disease, prior anti-cancer treatment, relapse date, death date and follow up dates, past and concurrent medical history, and concurrent medications at time of surgery. Primary outcome(s): Identification of a lymph node restricted CD8+ T cell population with a gene expression profile consistent with peripheral tolerance using single cell RNA sequence (scRNAseq) analysis of all obtained samples.[At completion of scRNAseq analysis of all obtained samples] Study Design: Timing: Prospective

Dataset Information

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance.

Publications

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance.

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