The effects of changes at peptide residues contacting MHC class II T-cell receptor on antigen recognition and human Th0 cell effector function

J. R. Lamb, J. A. Higgins, C. Hetzel, J. D. Hayball, R. A. Lake, R. E. O'Hehir

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Abstract

Cytokines can influence the selection of functional subsets (Th1 or Th2) of CD4+ T cells. However, quantitative changes in affinity of peptide/major histocompatibility complex (MHC) class II/T-cell receptor (TCR) interactions may alter antigen density and modulate T-cell effector function. The possibility exists to use peptide analogues to induce a partial signal to dissociate production of interleukin-4 (IL-4) and interferon-γ (IFN-γ) by T-helper type-0 (Th0) cells and, consequently, to regulate T-cell function. Based on binding assays and resolution of the crystalline structure of an influenza virus haemagglutinin peptide (HA 306-318) bound to the human MHC class II molecule DRB1*0101, we synthesized HA peptide analogues with amino acid substitutions predicted to modify either MHC class II/peptide density or TCR/peptide interactions. When we examined their antigenicity using cloned human Th0 cells, the analogues, in general, elicited a gradation in potency reflected by a reduction in both proliferation and cytokine production (IL-2, IL-4 and IFN-γ). Although the analogue HA R309 diminished IL-2 production, none of the analogues tested could selectively induce only IL-4 or IFN-γ. Since, in general, the effector functions of the Th0 cells examined here were resistant to selective manipulation by the peptide analogues, this suggests that for some clones of chronically activated T cells modulation of selected functions may be difficult to achieve.

Original languageEnglish
Pages (from-to)447-454
Number of pages8
JournalImmunology
Volume85
Issue number3
Publication statusPublished - 1 Jan 1995
Externally publishedYes

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