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.
authors: Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham B15 2TT, UK.
authors: Chun Jing
authors: CJ
authors: Wang
authors: Emily M
authors: EM
authors: Schmidt
authors: Kesley
authors: K
authors: Attridge
authors: Rupert
authors: R
authors: Kenefeck
authors: Lukasz
authors: L
authors: Wardzinski
authors: Jayne L
authors: JL
authors: Chamberlain
authors: Annelise
authors: A
authors: Soulier
authors: Louise E
authors: LE
authors: Clough
authors: Claire N
authors: CN
authors: Manzotti
authors: Parth
authors: P
authors: Narendran
authors: Lucy S K
authors: LS
authors: Walker
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D060908:CTLA-4 Antigen