Altered peptide ligands: Prospects for immune intervention in autoimmune disease

Abstract

It has long been accepted that the response of T cells to a protein antigen is strongly influenced by parameters governing processing and presentation of the immunodominant epitopes. Recent evidence has suggested, however, that subtle changes in the nature of the ligand itself may also affect the outcome of T-cell receptor (TCR) ligation, necessitating a re-evaluation of previously accepted paradigms of T-cell activation. In particular, activation may no longer be regarded as an all-or-nothing event, but appears to involve both quantitative and qualitative dimensions. This revolution in our understanding has emanated from the recent discovery that analogues of immunogenic peptides, so-called altered peptide ligands (APLs), may elicit a subset of normal activation events, or profoundly influence responses to the wild-type epitope. As such, the potential offered by APLs for modifying the outcome of deleterious immune responses involved in autoimmunity has not passed unnoticed. Indeed, the design and exploitation of novel reagents based on the structure of autoantigenic epitopes has enjoyed some measure of success in the treatment of experimental models of autoimmune disease and holds promise for their exploitation within the clinical arena.

Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby

“…Far from responding to antigen stimulation in a binary fashion, T cells have since been shown to mount a continuum of responses, the individual components of which may be effectively uncoupled by introducing subtle changes in the TCR contact sites of their cognate ligand (10). The additional demonstration that certain APLs may act as competitive antagonists of the TCR (11) has raised interest in harnessing their properties for immune intervention in a variety of autoimmune and alloimmune settings (9,23,42). Nevertheless, despite early success in rodent models of autoimmune disease (14)(15)(16)(17)(18)(19), the problems of antagonizing a polyclonal T cell repertoire in the face of determinant spreading have yet to be surmounted, greatly complicating the application of such an approach to the clinic (43).…”

“…To determine the relative affinity of APLs for their H-2E k restriction element, a competition binding assay was developed using, as a readout, IL-2 release by the 2G7.1 T cell hybridoma (53), specific for HEL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] in the context of H-2E k . The B cell lymphoma cell line, CH27, was lightly fixed in 0.5% paraformaldehyde, and 5 × 10 4 cells were added per well of a 96-well flat-bottomed plate.…”

“…The T cell hybridoma 2G7.1 is specific for the 1-18 epitope of hen egg lysozyme (HEL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] in the context of H-2E k and responds to stimulation by secretion of IL-2. The B cell lymphoma CH27 was lightly fixed with paraformaldehyde and pulsed with various concentrations of either Dbx or Dby for 1 hour before the addition of 0.5 μM HEL [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and the 2G7.1 hybridoma. Figure 1B shows the levels of IL-2 detected by ELISA in the culture supernatant 24 hours later.…”

“…Although for many years the T cell response to foreign antigen was considered to be all or nothing, subtle changes in the T cell receptor (TCR) contact residues of dominant epitopes have revealed that a broad spectrum of responses may be elicited from the same population of cells (8,9). While some APLs have been found to act as partial agonists, stimulating a subset of normal activation events (10), others perform the function of competitive antagonists (11) or induce long-term anergy among responding T cells (12).…”

Automatic Sequence Design of Major Histocompatibility Complex Class I Binding Peptides Impairing CD8+ T Cell Recognition

“…other T cell subsets (12)(13)(14)(15)(16). Design of novel peptides with both high HLA binding affinity and capable of targeting specific HLA alleles can therefore also be used for modulating the immune system.…”