Over coming the crypticity of a viral T cell Determinant by insertion into a chimeric bacterial protein

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Abstract
Among the potential T cell determinants contained In a protein antigen, the T cell response only focuses on a few immunodomlnant T cell determinants, whereas cryptic epitopes remain hidden to the Immune system. In the present work, we have studied the antigen processing and presentation of the C3: 93-115 sequence of Mahoney pollovlrus VP1 protein, which Is Immunodomlnant In H-2d but cryptic In H-2s and H-2q mouse MHC haplotypes. For this purpose, we genetically Inserted the C3 determinant Into five internal sttes of a bacterial protein, the maltose binding protein of Escherichla coll (MalE). In four out of five Insertion sites of MalE, the C3 determinant retained Its Immunodominance when the purified hybrid proteins were Injected to BALB/c (H-2d) mice. Moreover, In SJL/J (H-2d) mice, in three out of five MalE-C3 constructs, the new structural environment of the cryptic C3 epltope rescued Its processing and its in vivo presentation to T cells. In contrast, In DBA/1 (H-2d) mice, although MalE-C3 chimeric proteins were correctly processed in vitro, the C3 epitope remained cryptic in vivo. In this case, the impairment to stimulate a T cell response in vivo was correlated with a short time persistence of C3 peptides bound to Aq molecules at the surface of live antigen-presenting cells. These results emphasize the role of flanking residues on the lack of processing of cryptic determinants and the Importance of the life span of peptlde-MHC complexes to stimulate T cell responses.

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