Kinetics and thermodynamics of T cell receptor-autoantigen interactions inmurine experimental autoimmune encephalomyelitis

In the current study, cellular and molecular approaches have been used to a nalyze the biophysical nature of T cell receptor (TCR)peptide MHC(pMHC) int eractions for two autoreactive TCRs. These two TCRs recognize the N-termina l epitope of myelin basic: protein (MBP1-11) bound to the MHC class II prot ein. I-AU, and are associated with murine experimental autoimmune encephalo myelitis. Mice transgenic for the TCRs have been generated and characterize d in other laboratories. These analyses indicate that the mice either devel op encephalomyelitis spontaneously (172.10 TCR) or only if immunized with a utoantigen in adjuvant (1934.4 TCR). Here, we show that the 172.10 TCR bind s MBP1-11:I-A(u) with a 4-5-fold higher affinity than the 1934.4 TCR, Consi stent with the higher affinity, 172.10 T hybridoma cells are significantly more responsive to autoantigen than 1934.4 cells. The interaction of the 17 2.10 TCR with cognate ligand is more entropically unfavorable than that of the 1934.4 TCR, indicating that the 172.10 TCR undergoes greater conformati onal rearrangements upon ligand binding. The studies therefore suggest a co rrelation between the strength and plasticity of a TCR-pMHC interaction and the frequency of spontaneous disease in the corresponding TCR transgenic m ice. The comparative analysis of these two TCRs has implications for unders tanding autoreactive T cell recognition and activation.