Competition Between Two MHC Binding Registers in a Single Peptide Processed from Myelin Basic Protein Influences Tolerance and Susceptibility to Autoimmunity

Abstract

Experimental allergic encephalomyelitis (EAE) is an animal model for multiple sclerosis induced by stimulating myelin basic protein (MBP)-specific T cells. The MBP-specific repertoire in B10.PL mice is shaped by tolerance mechanisms that eliminate MBP121–150–specific T cells. In contrast, MBPAc1–11–specific T cells escape tolerance and constitute the encephalitogenic repertoire. To determine if this differential tolerance is caused by differences in the abundance of MBP epitopes generated by processing, MBP peptides were eluted from I-Au complexes and analyzed by mass spectrometry. Peptides were identified from both the NH2-terminal and MBP121–150 regions. Unexpectedly, MBPAc1–18 and Ac1–17, which contain the MBPAc1–11 epitope, were much more abundant than MBP121–150 peptides. The results demonstrate that competition between two I-Au binding registers, a low affinity register defined by MBPAc1–11 and a high affinity register defined by MBP5–16, prevents most of the NH2-terminal naturally processed peptides from binding in the MBPAc1–11 register. The small fraction of MBPAc1–18 bound in the MBPAc1–11 register is not sufficient to induce tolerance but provides a ligand for MBPAc1–11–specific T cells during disease. These results provide a basis for both the lack of tolerance to MBPAc1–11 and the ability of this epitope to become a target during autoimmunity.

The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form

“…First, why is the 9 -23 segment of the insulin B chain a central focus of the T cell response? An explanation may lie in the studies from Goverman's laboratory (38) on the response to myelin basic protein. Their data suggest that a different segment of the protein binds with high affinity and the T cells to it are negatively selected.…”

Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis

“…It remains questionable whether these T cells can be activated with the autoantigen in vivo or whether they rather represent cross-reactive cells specific for different nominal Ags and are mostly unrelated to the autoimmune processes. The emerging animal studies suggest that the latter is true (13,21), and our clinical experience with an altered peptide ligand of MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] demonstrated that disease-mediating T cells recognized the native MBP peptide with unexpectedly high functional avidities (22,23).…”

“…1B, second panel). However, only several myelin epitopes contributed to the increased reactivity observed in MS patients: MBP epitopes (MBP [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] , MBP 111-129 , and MBP 146 -170 ), PLP 139 -154 , and MOG (MOG [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and MOG ) (Fig. 1B).…”

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

“…Fourier Transform instrumentation also enables estimation of relative abundance of different peptides [24,25], providing an additional dimension of information for use in understanding how the immune system discriminates important antigens. Combined ion-trap and Fourier Transform instrumentation also makes it possible to compare the dominant peptides in two samples, identify differences, and sequence them -a true "differential peptide display" technique [66,85,147]. This approach has been substantially enhanced through the use of stable isotope labeling, enabling the identification of peptides selectively displayed by MHC molecules on cancer and infected cells [148][149][150][151][152].…”