An altered peptide ligand specifically inhibits Th2 cytokine synthesis by abrogating TCR signaling.
Altered peptide ligands (APL) can modify T cell effector function by their diversity in binding to the TCR or MHC class II-presenting molecules. The capacity to inhibit Th2 cytokine production by allergen-specific T cells would contribute to combating allergic inflammation. The presence of APL generated by Ala-substitutions in a synthetic dodeca-peptide spanning an immunodominant epitope of bee venom phospholipase A2 (PLA) was investigated in human T cells. Four of five substituted peptides reduced proliferation, IL-4, and IFN-gamma production by cloned PLA-specific Th0 cells proportionately. However, one APL, PLA-F82A, inhibited IL-4 but had no effect on IFN-gamma production. This uncoupling of IL-4 from IFN-gamma production was also observed on immunogenic restimulation of the cloned T cells pre-exposed to the APL/APCs. It appeared to result from lower affinity of binding to MHC class II by the APL compared with the native peptide. The APL also inhibited IL-4 production by polyclonal T cells. In consequence of the change in cytokine secretion, the production of IgG4 in vitro increased by PLA-F82A stimulation, compared with the native peptide. Exposure of the cloned T cells to either the APL or the native peptide, in the absence of professional APC, induced anergy such that proliferation and production of IL-4, IL-5, and IL-13 was abrogated on immunogenic rechallenge. Defective T cell activation appeared to result from alterations in transmembrane signaling through the TCR, specifically to lack of tyrosine phosphorylation of the tyrosine kinase, ZAP-70.
Faith
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Swiss Institute of Allergy and Asthma Research, Davos, Switzerland. siaf@siaf.unizh.ch
Akdis
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CA
Akdis
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M
Joss
A
A
Wymann
D
D
Blaser
K
K
D017635:Clonal Anergy; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis*; D006682:HLA-DP Antigens / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D010741:Phospholipases A / Q000276:immunology; D054467:Phospholipases A2; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase