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
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
SN - 1520-7560
VL - 27
SP - 946
EP - 950
JO - Diabetes/metabolism research and reviews
JF - Diabetes/metabolism research and reviews
IS - 8
ER -