A chimeric TCR-beta chain confers increased susceptibility to EAE.
Autoreactive myelin-specific CD4(+) T cells play an important role in CNS demyelination observed in MS and EAE. Consequently, it is important to understand the mechanisms of T cell receptor signalling leading to the activation of autoreactive T cells. We have previously generated a chimeric T cell receptor beta-chain (betaIII) displaying increased antigen sensitivity by exchanging most of the transmembrane and the intracellular domain of the TCR-beta chain with the corresponding TCR-gamma sequence. To investigate the effect of this "super-signalling" TCR in an autoimmune setting, we generated MOG(35-55) specific TCR transgenic mice expressing either the wild-type or the chimeric betaIII TCR-beta chain. We found that naïve transgenic T cells expressing the chimeric betaIII chain proliferated more extensively than wild-type cells in response to MOG(35-55)in vitro. Likewise, betaIII T cells skewed into a TH1 phenotype maintained the proliferative advantage over wild-type TH1 T cells at low antigen concentration. However, when skewed into a TH2 phenotype, there was no difference in proliferation between wild-type and betaIII T cells. Blocking of Fas-mediated cell death evenly affected wild-type and betaIII TH1 T cells and resulted in increased proliferation of both subsets, suggesting that betaIII T cells did not show defective Fas-FasL signalling. Finally, we found that betaIII TCR transgenic mice are more susceptible to EAE than wild-type TCR transgenic mice. We conclude that the change in the transmembrane domain of the TCR-beta chain affects TH1 T cells and the susceptibility to EAE, but does not affect TH2 cells. Investigating the molecular interaction within the TCR complex will help us to identify signalling pathways that can be manipulated to stop the progression of MS.
Petersen
Troels R
TR
Malaghan Institute of Medical Research, P.O. Box 7060, Wellington South, New Zealand.
Lata
Roleen
R
Spittle
Evelyn
E
Bäckström
B Thomas
BT
D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004198:Disease Susceptibility / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
C491901:FAS protein, human; D053222:Fas Ligand Protein; D006023:Glycoproteins; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D019014:fas Receptor; C445081:myelin oligodendrocyte glycoprotein (35-55); D015847:Interleukin-4; D007371:Interferon-gamma