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Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
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-
production by cloned PLA-specific Th0 cells
proportionately. However, one APL, PLA-F82A, inhibited IL-4 but had no
effect on IFN- production. This uncoupling of IL-4 from IFN-
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.
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