Alteration at a Single Amino Acid Residue in the T Cell Receptor α Chain Complementarity Determining Region 2 Changes the Differentiation of Naive Cd4 T Cells in Response to Antigen from T Helper Cell Type 1 (Th1) to Th2

To study whether changes in the structure of a T cell receptor (TCR) at a single peptide-contacting residue could affect T cell priming with antigenic peptide, we made transgenic mice with a point mutation in the TCR α chain of the D10.G4.1 (D10) TCR and bred them to D10 β chain transgenic mice. The mutation consisted of a leucine to serine substitution at position 51 (L51S), which we had already established contacted the second amino acid of the peptide such that the response to the reference peptide was reduced by ∼100-fold. A mutation in the reference peptide CA134–146 (CA-WT) from the arginine at peptide position 2 to glycine (R2G) restored full response to this altered TCR. When we examined in vitro priming of naive CD4 T cells, we observed that the response to doses of CA-WT that induced T helper cell type 1 (Th1) responses in naive CD4 T cells from mice transgenic for the D10 TCR gave only Th2 responses in naive CD4 T cells derived from the L51S. However, when we primed the same T cells with the R2G peptide, we observed Th1 priming in both D10 and L51S naive CD4 T cells. We conclude from these data that a mutation in the TCR at a key position that contacts major histocompatibility complex–bound peptide is associated with a shift in T cell differentiation from Th1 to Th2.