Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Tan, PH; Yates, JB; Xue, S-A; Chan, C; Jordan, WJ; Harper, JE; Watson, MP; Dong, R; Ritter, MA; Lechler, RI; Lombardi, G; George, AJT

Published Date

  • November 1, 2005

Published In

Volume / Issue

  • 106 / 9

Start / End Page

  • 2936 - 2943

PubMed ID

  • 15994283

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-05-1826

Language

  • eng

Conference Location

  • United States