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Weisan Chen^*, Jonathan W. Yewdell^*, Rodney L. Levine, and Jack R. Bennink^*

From the ^* Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, and the Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-0440

In studying the subdominant status of two cysteine-containing influenza virus nuclear protein (NP) determinants (NP_39–47 and NP_218–226) restricted by H-2K^d, we found that the antigenicity of synthetic peptides was enhanced 10–100-fold by treatment with reducing agents, despite the fact that the affinity for K^d was not enhanced. Reducing agents also markedly enhanced the immunogenicity of cysteine-containing peptides, as measured by propagation of long-term T cell lines in vitro. Similar enhancing effects were obtained by substituting cysteine with alanine or serine in the synthetic peptides, demonstrating that sulfhydryl modification of cysteine is responsible for the impaired antigenicity and immunogenicity of NP_39–47 and NP_218–226. We found similar effects for two widely studied, cysteine-containing peptides from lymphocytic choriomeningitis virus. The major modifications of cysteine-containing synthetic peptides are cysteinylation and dimerization occurring through cysteine residues. We demonstrate that both of these modifications occur in cells synthesizing a cytosolic NP_218–226 minigene product and, further, that T cells specific for cysteinylated NP_218–226 are induced by influenza virus infection in mice, demonstrating that this modification occurs in vivo. These findings demonstrate that posttranslational modifications affect the immunogenicity and antigenicity of cysteine-containing viral peptides and that this must be considered in studying the status of such peptides in immunodominance hierarchies.

Key Words: antigen processing • cysteine/immunology • major histocompatibility complex/immunology • viral vaccines/immunology • peptides/immunology

Bethany Buschling provided outstanding technical assistance.

W. Chen was supported by a C.J. Martin Fellowship (967036) from the Australian National Health and Medical Research Council.

Abbreviations used: ER, endoplasmic reticulum; FBS, fetal bovine serum; LCMV, lymphocytic choriomeningitis virus; NP, nuclear protein; RP-HPLC, reversed-phase HPLC; VV, vaccinia virus.

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