Differential activation of ERK, p38, and JNK required for Th1 and Th2 deviation in myelin-reactive T cells induced by altered peptide ligand

Autoreactive T cells can be induced by altered peptide ligands to switch Th1 and Th2 phenotypes. The underlying molecular mechanism is critical for understanding of activation of autoreactive T cells and development of novel therapeutic strategies for autoimmune conditions. In this study, we demonstrated that analog peptides of an immunodominant epitope of myelin basic protein (residues 83-99) with alanine substitution at Val(86) and His(88) had a unique partial agonistic property in the induction of Th1 or Th2 deviation in MBP83-99-reactive T cell clones typical of Th0 phenotype. The observed. phenotypic switch involved differential activation of ERK, p38, and JNK MAPKs. More specifically, Th1 deviation induced by peptide 86V --> A (86A) correlated with enhanced p38 and JNK activities, while Th2 deviation by peptide 88H-A (88A) was associated with up-regulated ERK activity and a basal level of p38 and JNK activity. Further characterization revealed that a specific inhibitor for ERK selectively prevented Th2 deviation of MBP83-99-specific T cells. Conversely, specific inhibitors for p38 and JNK blocked Th1 deviation in the same T cell preparations induced by peptide 86A. The findings have important implications in our understanding of regulation of ERK, p38, and JNK by altered peptide ligands and their role in cytokine regulation and phenotype switch of autoreactive T cells.