A chimeric T cell receptor with super-signaling properties.
A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-alphabeta chains result in the activation of distinct signal transduction pathways by the CD3-gammadeltaepsilon/zeta complex? To investigate which part of the TCR-beta chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-beta chain with the corresponding TCR-gamma chain domains. We show here that hybridoma cells expressing a chimeric TCR-beta chain (betaIII) containing intracellular and transmembrane TCR-gamma amino acids, together with a wild-type TCR-alpha (alphawt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-alphawt/betawt chains. This super-signaling phenotype of the betaIII chain was observed in two different TCRs. One specific for an alloantigen (I-A(bm12)) and one for an autoantigen (I-A(b)/MOG(35-55)). We found that this chimeric alphawt/betaIII TCR had normal association with CD3-gammadeltaepsilon and zeta chains. To investigate the effect of the chimeric betaIII chain in transgenic T cells, we made MOG(35-55)-specific TCR transgenic mice expressing either the alphawt/betawt or chimeric alphawt/betaIII TCR. Similar to what was observed in hybridoma cells, transgenic alphawt/betaIII 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.
Petersen
Troels R
TR
Malaghan Institute of Medical Research, Wellington, New Zealand.
Gülland
Sven
S
Bettelli
Estelle
E
Kuchroo
Vijay
V
Palmer
Ed
E
Bäckström
B Thomas
BT
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D007519:Isoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011993:Recombinant Fusion Proteins