An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction

Abstract

The peptide rAc1-11 represents the dominant T cell epitope of rat myelin basic protein (MBP) in mice of the H-2u haplotype. Residue 4 has been shown previously to govern binding of the peptide to the class II molecule, I-Au. We have constructed peptide analogues bearing amino acid substitutions at position 4 and have assessed their ability to stimulate an antigen-specific T cell hybridoma when presented by viable antigen presenting cells (APC). Complexes between I-Au and one such analogue, rAc1-11[4A], were rapidly lost from the surface of live APC displaying a half-life (t 1/2) of approximately 10 min. Neither shedding of intact complexes from the cell surface, nor their internalization and recycling through an acidic intracellular compartment were found to account for their loss. The possible dissociation of rAc1-11[4A] from the peptide binding cleft was therefore addressed by comparing the t 1/2 of complexes between I-Au and peptide analogues of higher affinity. The tyrosine-substituted analogue, rAc1-11[4Y], remained stably bound to I-Au for at least 4 h, thereby displaying a t 1/2 far in excess of that evident for rAc1-11[4A]. Significantly, the wild type peptide, rAc1-11, bound so transiently that functional complexes could not be detected on the surface of peptide-pulsed APC. The physiological relevance of these findings was confirmed by extending our studies to an analysis of the homologous epitope of murine MBP; evidence that this epitope likewise displays minimal affinity for I-Au suggests a novel strategy for the escape from tolerance induction by encephalitogenic T cells.

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

“…The extent and specificity of these self peptide-MHC complexes in facilitating activation of antigen-specific T cells needs to be examined in greater detail. As a side note, earlier work in the experimental autoimmune encephalomyelitis model had also suggested a relationship between low affinity peptides and T cell autoreactivity [46,47]. In this inducible disease model, the autoantigenic peptide, Ac1-11 of myelin basic protein, bound poorly to the class II MHC molecule, I-A u , and autoreactive T cells were shown to escape negative selection in the thymus [46,47].…”

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

“…In the case of the diabetic NOD mouse, previous studies (36,37) identified a high number of autoreactive T cells. These were attributed to the I-A g7 molecule, indicating that this MHC molecule in general had a propensity for high autoreactivity.…”

Weak Proinsulin Peptide–Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice

“…The PI-1(47-64) epitope represents a striking example of a very poor binding MHC ligand, IC 50 values ϳ100 mol/l, that gives rise to T-cells capable of causing diabetes in adoptive transfer experiments. The relationship between poor peptide-MHC binding and the fostering of an autoimmune, pathogenic T-cell repertoire has been suggested in studies on experimental allergic encephalomyelitis (7,8) and in our recent work on the insulin ␤-chain (9 -23) epitope (2) and in other model systems (9 -11).…”

“…The relationship of low affinity of a peptide to an MHC molecule and autoimmune reactivity has also been noted in the encephalitogenic peptide from myelin basic protein (7,8). This has led to the speculation that low-affinity peptides may not be conducive to the normal mechanisms in the thymus that control autoreactivity.…”