Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model.

Research output: Contribution to journalArticle

Standard

Harvard

APA

Vancouver

Author

Bibtex

@article{0cb2f712222743a78dfdf31ab0cb5e9c,
title = "Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model.",
abstract = "BACKGROUND The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed. METHODS Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11 × RIP-mOVA diabetes model and the role of CTLA-4 in Treg function. RESULTS Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11 × RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells. CONCLUSIONS These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation. Copyright {\textcopyright} 2011 John Wiley & Sons, Ltd.",
author = "CJ Wang and EM Schmidt and Kesley Attridge and Rupert Kenefeck and Lukasz Wardzinski and Jayne Chamberlain and A Soulier and LE Clough and Claire Manzotti and Partheepan Narendran and Lucy Walker",
year = "2011",
month = nov,
day = "1",
doi = "10.1002/dmrr.1277",
language = "English",
volume = "27",
pages = "946--50",
journal = "Diabetes/metabolism research and reviews",
issn = "1520-7552",
publisher = "Wiley",
number = "8",

}

RIS

TY - JOUR

T1 - Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model.

AU - Wang, CJ

AU - Schmidt, EM

AU - Attridge, Kesley

AU - Kenefeck, Rupert

AU - Wardzinski, Lukasz

AU - Chamberlain, Jayne

AU - Soulier, A

AU - Clough, LE

AU - Manzotti, Claire

AU - Narendran, Partheepan

AU - Walker, Lucy

PY - 2011/11/1

Y1 - 2011/11/1

N2 - BACKGROUND The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed. METHODS Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11 × RIP-mOVA diabetes model and the role of CTLA-4 in Treg function. RESULTS Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11 × RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells. CONCLUSIONS These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation. Copyright © 2011 John Wiley & Sons, Ltd.

AB - BACKGROUND The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed. METHODS Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11 × RIP-mOVA diabetes model and the role of CTLA-4 in Treg function. RESULTS Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11 × RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells. CONCLUSIONS These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation. Copyright © 2011 John Wiley & Sons, Ltd.

U2 - 10.1002/dmrr.1277

DO - 10.1002/dmrr.1277

M3 - Article

C2 - 22069290

VL - 27

SP - 946

EP - 950

JO - Diabetes/metabolism research and reviews

JF - Diabetes/metabolism research and reviews

SN - 1520-7552

IS - 8

ER -