International Immunology, Vol. 15, No. 5, pp. 665-677,
May 2003
© 2003 Japanese Society for Immunology
Clustering of immunoreceptor tyrosine-based activation motif-containing signalling subunits in CD4+ T cells is an optimal signal for IFN-
production, but not for the production of IL-4
1 Bone and Joint Research Unit, St Bartholomew’s and Royal London School of Medicine and Dentistry, Queen Mary, University of London, London EC1M 6BQ, UK 2 Max Planck Institute for Immunobiology, Freiburg D-79011, Germany 3 Present address: Biological Sciences Department, Imperial College London, London SW7 2AZ, UK
Correspondence to: Y. Chernajovsky; E-mail: y.chernajovsky{at}qmul.ac.uk
Transmitting editor: D. Wallach
CD4+ T cells with pre-defined MHC-unrestricted specificity to type II collagen (CII) were engineered for cell-based anti-inflammatory gene therapy of autoimmune arthritis. To this end, recombinant chimeric immunoreceptors, C2
or C2
, were expressed in primary mouse keyhole limpet hemocyanin (KLH)-specific Th1 and Th2 cells using retrovirus vector-based somatic cell gene transfer. The ectodomain of these tyrosine-based activation motif (ITAM)-containing immunoreceptors is a single-chain IgG variable domain of an anti-CII mAb. The engineered cells might arrest migration when they encounter CII in articular cartilage. Up to 19 and 55% of transduced CD4+ T cells expressed respectively C2 and C2. The expression of C2 or C2 on the surface of CD4+ T cells was down-regulated upon binding CII, and cells activated in such a way proliferated, up-regulated CD25 expression and produced cytokines. Comparison of cytokine levels normalized by the number of producer cells revealed that C2 and C2 were as potent as TCR in the induction of IFN-, but induced lower levels of IL-4. It appears that the reason why CD4+ T cells stimulated through C2 and C2 produce low levels of IL-4 is a lack of integration between co-stimulatory signals required for the optimal production of this cytokine and the ITAM-dependent signals generated by the immunoreceptors. The significance of these data for the development of anti-inflammatory gene therapy based on CD4+ T cells targeted to a tissue-specific protein is discussed.
Keywords: cytokine, gene therapy, mouse, TCR, Th1, Th2
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