Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression.
Activation of T lymphocytes requires the recognition of peptide-major histocompatibility complexes (MHCs) and costimulatory signals provided by antigen-presenting cells (APCs). It has been shown that T-cell activation without costimulation 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 cytotoxic T lymphocyte antigen 4 (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 up-regulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-immunoglobin (Ig). This gene-based strategy to knock out surface receptors is an attractive alternative to using immature dendritic cells for preventing transplant rejection and treating of autoimmune diseases.
Tan
Peng H
PH
Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, United Kingdom.
Yates
John B
JB
Xue
Shao-An
SA
Chan
Cliburn
C
Jordan
William J
WJ
Harper
Jennifer E
JE
Watson
Martin P
MP
Dong
Rong
R
Ritter
Mary A
MA
Lechler
Robert I
RI
Lombardi
Giovanna
G
George
Andrew J T
AJ
D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human