Implications of myelin basic protein processing and presentation on T cell activation and tolerance
Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis which can be induced by immunization with myelin antigens such as myelin basic protein (MBP). Immune tolerance influences the repertoire of MBP-specific T cells in B10.PL mice. MBPAc1--11-specific T cells escape tolerance while MBP121--150-specific T cells undergo tolerance in vivo. This differential tolerance induction may reflect unstable binding of MBPAc1--11 to I-Au compared to stable binding of peptides within MBP121--150.To determine which MBP epitopes are naturally processed from whole MBP, peptides eluted from I-Au isolated from MBP-pulsed splenocytes were analyzed by mass spectrometry. Two nested sets of peptides were found, N-terminal MBP peptides and peptides containing MBP125--135. N-terminal peptides MBPAc1--18 and MBPAc1--17 were the most abundant peptides processed from whole MBP. Our investigations indicate that MBPAc1--18 can bind in the register that presents MBPAc1--11, however, most MBPAc1--18 binds in a more stable register, MBP5--16, allowing MBPAc1--11-specific T cells to escape tolerance. Additionally, endogenously derived MBP peptides are constitutively presented by B cells and dendritic cells (DCs) which are able to stimulate activated MBP121--150-specific T cells. However, only DCs are able to stimulate naive MBP121--150-specific T cells, implicating DCs as the antigen presenting cell involved in the maintenance of peripheral tolerance to MBP.To investigate why two different MBPAc1--11-specific T cell receptor transgenic mouse lines exhibit differences in spontaneous EAE incidence, T cell responses to MBP were compared between the two lines. While differences in T cell proliferative responses were not detected, T cells isolated from the Tg line with lower spontaneous EAE incidence did not produce IFN-gamma and lower percentages of T cells produced cytokines compared to the line with higher incidence of spontaneous EAE.We also analyzed the structural basis for cross-reactivity exhibited by T cells recognizing two distinct epitopes within MBP121--150. Mutational analysis of the CDRI and 3 regions of one cross-reactive T cell receptor indicated that the same amino acids within CDR1 and 3 are used to recognize both epitopes.