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Processing and Reactivity of T Cell Epitopes Containing Two Cysteine Residues from Hen Egg-White Lysozyme (HEL_74–90)¹

Hee-Kap Kang^2,*, John A. Mikszta23^*, Hongkui Deng^4,, Eli E. Sercarz^5,, Peter E. Jensen and Byung S. Kim^6,*

^* Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611; Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90024; and Department of Pathology, Emory University, Atlanta, GA 30322

The Ag processing and structural requirements involved in the generation of a major T cell epitope from the hen egg-white lysozyme protein (HEL_74–88), containing two cysteine residues at positions 76 and 80, were investigated. Several T cell hybridomas derived from both low responder (I-A^b) and high responder (I-A^k) mice recognize this region. These hybridomas are strongly responsive to native HEL, but unresponsive to the reduced and carboxymethylated protein. Air-oxidized HEL_74–88 peptide was unable to bind I-A^k molecules and failed to stimulate T cells in the absence of intracellular Ag processing. Further functional competition assays showed that alkylation of cysteine residues with bulky methyl groups interferes with the contacts for the MHC class II molecules (I-A^k) of high responder mice and the I-A^b-restricted TCR of low responder mice. Serine substitutions of the cysteine residues of HEL_74–88 either enhanced or abrogated T cell stimulation by the peptides without significant alterations in the class II binding. These results suggest that the cysteine residues of peptides must be free from disulfide bonding for efficient stimulation of T cells and yet frequently used modifications of cysteine residues may not be suitable for peptide-based vaccine development.

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