The nature of cryptic epitopes within the self-antigen myelin basic protein

Abstract

Mechanisms that allow potentially autoreactive T cells to escape central tolerance and persist in the peripheral lymphoid organs of healthy individuals are poorly defined. It has been proposed that such cells are specific for epitopes which normally are not well presented to the immune system or, in other words, are cryptic. We have used synthetic peptides to define potential T cell epitopes within the N-terminal portion of myelin basic protein (MBP). These were defined in terms of their relative affinity for the MHC-restriction element I-Au and their ability to activate T cells in mice of the H-2(u) haplotype. Three epitopes were identified, one of which corresponded to the known dominant N-terminal epitope (Ac1-9). The other two epitopes (9-20 and 5-20) bound to their MHC-restriction element with relatively high affinity but were cryptic, as defined by the poor response to these epitopes following immunization with intact MBP. Even the longer of these two epitopes did not induce autoimmune encephalomyelitis in H-2(u) mice. These results demonstrate that antigen processing can control both the induction of and effector function of autoreactive T cells, and is therefore a principal mechanism involved in limiting the autoreactive T cell repertoire.

Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

“…and then examined the thymus rather than directly looking at fetal thymic organ culture. Our results are directly complementary to those described recently by Garcia and colleagues (11), Additionally, we provide direct evidence, by using LDVM1-9-specific T cells, for the existence of an N-terminal LDVM register in addition to the C-terminal register previously described (14), as well as demonstrating competition at the same site within the I-A u groove. Our results also make use of the self (murine) sequence of MBP rather than the foreign guinea pig sequence used by Garcia and colleagues.…”

“…In addition to the LDVM register, overlapping 1-9 on its left side, a right side flanking determinant which binds to I-A u has also been described (14). To study possible competitive capture by this right side flanking region, we prepared the peptide LDVMASQKRPSQRSKYLATA (ϭLDVM 1-16).…”

Identification of Cross-Reactive Peptides Using Combinatorial Libraries Circumvents Tolerance against Her-2/neu-Immunodominant Epitope

“…Considering that the interaction of the TCR with the peptide-MHC ligand is highly flexible and that the same TCR can recognize many different epitopes (20,21), several laboratories have demonstrated that amino acid alterations in T cell epitopes could enhance stimulation of T cell populations for the nominal epitope (22,23). The alteration of tumor-specific epitopes has become an attractive strategy for modifying immune responses and enhancing Ag-specific immunotherapies (24,25). The finding that a single alteration in the epitope can significantly enhance the antitumor effect raises the question of whether multiple alterations will have additive effects resulting in a more potent protection.…”

Recombinant Adenovirus Coexpressing Covalent Peptide/MHC Class II Complex and B7-1: In Vitro and In Vivo Activation of Myelin Basic Protein-Specific T Cells

“…This substitution was reported to increase the peptide affinity for I-A u (34,35), but does not appear to affect T cell recognition (36). The 1934.4 THy, specifically recognizing MBP [1][2][3][4][5][6][7][8][9][10][11] in the context of I-A u , was used to evaluate the efficiency of gene expression in infected cells.…”