A chimeric TCR-β chain confers increased susceptibility to EAE

Abstract

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 β-chain (βIII) displaying increased antigen sensitivity by exchanging most of the transmembrane and the intracellular domain of the TCR-β chain with the corresponding TCR-γ 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 βIII TCR-β chain. We found that naïve transgenic T cells expressing the chimeric βIII chain proliferated more extensively than wild-type cells in response to MOG 35–55 in vitro. Likewise, βIII 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 βIII T cells. Blocking of Fas-mediated cell death evenly affected wild-type and βIII TH1 T cells and resulted in increased proliferation of both subsets, suggesting that βIII T cells did not show defective Fas–FasL signalling. Finally, we found that βIII 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-β 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.