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

✍ Scribed by Chun Jing Wang; Emily M. Schmidt; Kesley Attridge; Rupert Kenefeck; Lukasz Wardzinski; Jayne L. Chamberlain; Annelise Soulier; Louise E. Clough; Claire N. Manzotti; Parth Narendran; Lucy S. K. Walker

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 491 KB
• Volume: 27
• Category: Article
• ISSN: 1520-7552
• DOI: 10.1002/dmrr.1277

✦ Synopsis

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 © 2011 John Wiley & Sons, Ltd.