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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2936-2943.
Prepublished online as a Blood First Edition Paper on June 30, 2005; DOI 10.1182/blood-2005-05-1826.
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Submitted May 5, 2005
Accepted June 15, 2005
Creation of tolerogenic human DC via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression
Peng H Tan, John B Yates, Shao-An Xue, Cliburn Chan, William J Jordan, Jennifer E Harper, Martin P Watson, Rong Dong, Mary A Ritter, Robert I Lechler, Giovanna Lombardi, and Andrew J George*
Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
* Corresponding author; email: a.george{at}imperial.ac.uk.
Activation of T lymphocytes requires the recognition of peptide-MHC complexes and co-stimulatory signals provided by antigen presenting cells (APCs). It has been shown that T cell activation without co-stimulation can lead to anergy. In this study, we developed a novel strategy to inhibit expression of B7 molecules (CD80/86) by transfecting APCs with a gene construct encoding a modified CTLA4 molecule (CTLA4-KDEL) that is targeted to the endoplasmic reticulum (ER). APCs expressing this construct failed to express CD80/86 on their surface, were unable to stimulate allogeneic and peptide-specific T cell responses and induced antigen specific anergy of the responding T cells. Cells expressing CTLA4-KDEL do not upregulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-Ig. This gene-based strategy to knockout surface receptors is an attractive alternative to using immature dendritic cells for preventing transplant rejection and treating of autoimmune diseases.
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