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International Immunology Advance Access originally published online on May 17, 2004
International Immunology 2004 16(7):889-894; doi:10.1093/intimm/dxh098
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International Immunology, Vol. 16, No. 7, pp. 889-894, July 2004
© 2004 Japanese Society for Immunology

FAST TRACK

A chimeric T cell receptor with super-signaling properties

Troels R. Petersen, Sven Gülland, Estelle Bettelli1, Vijay Kuchroo1, Ed Palmer2 and B. Thomas Bäckström

Malaghan Institute of Medical Research, Wellington, New Zealand 1 Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Laboratory of Transplantation Immunology and Nephrology, Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland

Correspondence to: B. T. Bäckström; Email: tbackstrom{at}malaghan.org.nz
Transmitting editor: S. Akira

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-{alpha}ß chains result in the activation of distinct signal transduction pathways by the CD3-{gamma}{delta}{epsilon}/{zeta} complex? To investigate which part of the TCR-ß chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-ß chain with the corresponding TCR-{gamma} chain domains. We show here that hybridoma cells expressing a chimeric TCR-ß chain (ßIII) containing intracellular and transmembrane TCR-{gamma} amino acids, together with a wild-type TCR-{alpha} ({alpha}wt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-{alpha}wt/ßwt chains. This super-signaling phenotype of the ßIII chain was observed in two different TCRs. One specific for an alloantigen (I-Abm12) and one for an autoantigen (I-Ab/MOG35–55). We found that this chimeric {alpha}wt/ßIII TCR had normal association with CD3-{gamma}{delta}{epsilon} and {zeta} chains. To investigate the effect of the chimeric ßIII chain in transgenic T cells, we made MOG35–55-specific TCR transgenic mice expressing either the {alpha}wt/ßwt or chimeric {alpha}wt/ßIII TCR. Similar to what was observed in hybridoma cells, transgenic {alpha}wt/ßIII T cells showed a super-signaling phenotype upon antigenic stimulation. Further studies may help us understand the effect of increased TCR signaling on autoimmunity and may lead to the identification of signaling molecules that can be targeted to stop the progression of autoimmune disorders such as multiple sclerosis.

Keywords: antigen signaling, structure–function, T cell receptor


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