Inhibition of altered peptide ligand‐mediated antagonism of human GAD65‐responsive CD4⁺ T cells by non‐antagonizable T cells

Abstract

Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4 + GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligandmediated antagonism is inhibited in a dose-dependent manner by the presence of nonantagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.

The potential of multimer technologies in type 1 diabetes prediction strategies

“…Saporin-coupled MHC tetramers were used to delete IGRP-reactive T cells in vitro and in vivo in NOD mice transgenic for IGRPreactive NY8.3 TCR [119]. The treatment was able to delay development and progression of the disease, nearly as effectively as low-affinity altered peptide administration in earlier studies [120][121][122]. Peptide treatment was only effective when initiated at 4 weeks of age and disease progression was unaltered when peptide treatment was initiated in a 10-week-old female NOD mice.…”

Antagonism of HIV-specific CD4+ T cells by C-terminal truncation of a minimum epitope

“…Antigen presenting cells (APCs) also likely play a role as activated APCs can mitigate the effects of antagonists (Kissler et al, 2002). More recent work has shown that exogenous IL-2 can reverse antagonism in human clones (Gebe et al, 2004). In summary, mechanisms of antagonism likely vary depending on the model system and specific epitope/MHC context, with at least some antagonists able to deliver a dominant negative signal, possibly through differential phosphorylation of intracellular signaling proteins.…”

A unique unresponsive CD4+ T cell phenotype post TCR antagonism

“…Although T cell antagonism has been extensively described [10, 17, 19, 26-28], the response of these antagonized cells to subsequent stimulation with wild type ligand has not yet been described. Previous studies have shown that under antagonist conditions, T cells exhibit a dose dependent decrease in proliferation to wild type stimulus [10, 17-19, 26-28], altered cytokine production [1, 29], and altered signaling [10, 12, 18].…”

“…Previous studies have shown that under antagonist conditions, T cells exhibit a dose dependent decrease in proliferation to wild type stimulus [10, 17-19, 26-28], altered cytokine production [1, 29], and altered signaling [10, 12, 18]. In order to assess the effects of T cell antagonism on subsequent T cell function, we have characterized the proliferative and cytokine responses of previously antagonized T cells to rechallenge with wild type ligand.…”