A chimeric T cell receptor with super-signaling properties

Abstract

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-αβ chains result in the activation of distinct signal transduction pathways by the CD3-γδE/ζ complex? To investigate which part of the TCR-β chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-β chain with the corresponding TCR-γ chain domains. We show here that hybridoma cells expressing a chimeric TCR-β chain (βIII) containing intracellular and transmembrane TCR-γ amino acids, together with a wild-type TCR-α (αwt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-αwt/βwt chains. This super-signaling phenotype of the βIII 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 αwt/βIII TCR had normal association with CD3-γδE and ζ chains. To investigate the effect of the chimeric βIII chain in transgenic T cells, we made MOG35-55-specific TCR transgenic mice expressing either the αwt/βwt or chimeric αwt/βIII TCR. Similar to what was observed in hybridoma cells, transgenic αwt/βIII 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. © 2004 The Japanese Society for Immunology.