Altered Peptide Ligand–Induced Partial T Cell Activation: Molecular Mechanisms and Role in T Cell Biology

Abstract

The elucidation of the phenomena of T cell antagonism and partial activation by altered peptide ligands has necessitated a revision in the traditional concepts of TCR recognition of antigen and subsequent signal transduction. Whereas previous models supported a single ligand specificity for any particular T cell, many studies using analogs of immunogenic peptides have now demonstrated a flexibility in this recognition. Moreover, interaction with such altered peptide ligands can result in dramatically different phenotypes of the T cells, ranging from inducing selective stimulatory functions to completely turning off their functional capacity. Investigations of the biochemical basis leading to these phenotypes have shown that altered peptide ligands can induce a qualitatively different pattern of signal transduction events than does any concentration of the native ligand. Such observations imply that several signaling modules are directly linked to the TCR/CD3 complex and that they can be dissociated from each other as a direct result of the nature of the ligand bound. Interestingly, many in vivo models of T cell activation are compatible with a selective signaling model, and several studies have shown that peptide analogs can play a role in various T cell biologic phenomena. These data strongly suggest that naturally occurring altered peptide ligands for any TCR exist in the repertoire of self-peptides or, in nature, derived from pathogens, and recent reports provide compelling evidence that this is indeed the case. The concept of altered peptide ligands, their effects on T cell signaling, the hypothesized mechanisms by which they exert their effects, and their possible roles in shaping the T cell immune response are the scope of this review.

Germinal Centers Regulate Human Th2 Development

“…In any way, the high content of anergic T cells within GCs suggests that these anatomical compartments also play a crucial role in controlling the duration and/or the magnitude of CD4 ϩ T cells responses. Activation of T cells requires both antigenic and costimulatory signals and in the absence of one of these they instead become anergized (59). A comprehensive expression of CD57 on purified CD4 ϩ T cells from blood can be obtained if these are stimulated with anti-CD28 mAb only (60).…”

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

“…Based on their ability to activate T cells, antigenic peptides can be grouped into different categories (11,12). Peptides that lead to complete activation of T cells are called full TCR agonists.…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…It is reported that CTLs induced by in vitro sensitization using the modified peptide exhibited better recognition of the native peptide compared with CTLs raised with the native peptide (82). Substitutions of amino acids of a peptide epitope, for example, can greatly increase the binding affinity without interfering with the peptide recognition (83)(84)(85)(86). Most of the immunogenic melanoma and melanocyte differentiation antigen peptides have a moderate or relatively low affinity for the HLAA*0201 molecule, in contrast to viral peptides that have high binding affinity for their corresponding MHC-I (87-90).…”