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The Amino Acid Sequences Flanking an Antigenic Determinant Can Strongly Affect MHC Class I Cross-Presentation without Altering Direct Presentation ¹

Fox Chase Cancer Center, Basic Sciences Division, Viral Pathogenesis Program, Philadelphia, PA 19111

Direct presentation (DP) and cross presentation (CP) on MHC I by professional APCs are defined by the internal or external source of the Ag, respectively. Although some Ags are substrates for both DP and CP, others are only substrates for DP. The reasons for this difference remain largely unknown. In this study, we studied in tissue culture and also in vivo, the effects of altering the length and sequence of the amino acid chains flanking an MHC class I restricted determinant (the chicken OVA OVA_258–265, SIINFEKL) that is normally a good substrate for both DP and CP. We demonstrate that CP but not DP strictly requires flanking N and C-terminal extensions of minimal length. Furthermore, we show that removal but not replacement of just one amino acid 22 residues downstream from the determinant is sufficient to strongly affect CP without affecting either protein stability or DP. Thus, our work shows that the flanking residues of an antigenic determinant can differentially affect CP and DP, and that features of the Ag other than half-life can have a major impact in CP. Our studies may have implications for understanding CP in viral infections and possibly for the design of new vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01AI048849 and R21AI058179 (to L.J.S.) and CA006927 to Fox Chase Cancer Center.

² X.M. and A.S. contributed equally to this work.

³ Current address: University of Michigan, 4013BSRB 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200

⁴ Address correspondence and reprint requests to Dr. Luis J Sigal, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: Luis.Sigal{at}fccc.edu

⁵ Abbreviations used in this paper: T_CD8⁺, CD8⁺ T lymphocyte; DP, direct presentation; pAPC, professional APC; CP, cross presentation; VACV, vaccinia virus; β-gal, β-galactosidase; M, macrophage; NP, nucleoprotein.