Cytokines elicited by T cell epitopes from a synovial autoantigen: Altered peptide ligands can reduce interferon‐γ and interleukin‐10 production

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Abstract
Objective To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp‐39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs). Methods Draining lymph node cells were harvested from HLA–DR*0401 transgenic mice that had been immunized with HC gp‐39. Cytokine responses to 5 previously identified HLA–DR*0401–restricted HC gp‐39 T cell epitopes were studied in vitro. The anchor and T cell receptor (TCR) contact residues of peptide 322–337 were identified, and this information was used to design alanine‐substituted APLs. T cells were primed in vivo with wild‐type peptide 322–337, restimulated with wild‐type peptide or APLs, and the cytokine profiles were compared. Results Restimulation with individual peptides elicited distinct cytokine profiles. HC gp‐39 (peptide 322–337) elicited a dominant interferon‐γ (IFNγ) response. Residues within the core (positions P1–P9) 322–337 peptide sequence were critical for T cell recognition. Surprisingly, the N‐terminal flanking region was also important for recognition by 6 of 10 specific T cell hybridomas. Substitutions of charged TCR contact residues in the 322–337 core epitope (E332A and K335A) were associated with a significant reduction in the IFNγ and interleukin‐10 (IL‐10) stimulation indices. Restimulation with peptides W325A and V326A was also associated with a trend toward reduced IFNγ and IL‐10 secretion. In contrast, restimulation with peptide D330N elicited cytokine profiles more comparable with those resulting from restimulation with wild‐type peptide. Conclusion This study indicates that APLs of a proinflammatory HC gp‐39 T cell epitope may be used to alter the cytokine response from a memory T cell population.
Funding Information
  • Arthritis Research Campaign (UK)
  • NIH (AR-44647, DK-54364, R01-AI-13587-26, AI-28809, AR-44647, DK-54364)
  • Arthritis Foundation