ELICITATION AND ENHANCEMENT OF T AND B CELL RESPONSES

摘要: The Major histocompatibility complex class I (MHC-I) has been characterized in such great depth that a number of its key properties are well understood and part behavior can even be predicted. It is therefore intriguing the impact small epitope modifications on immunogenicity elicitation T-cell repertoires remain often unpredictable full surprises. Substitution secondary anchor residue at peptide position 3 from serine to proline (p3P) significantly increased stabilization capacity melanoma-associated H-2D (D)-restricted gp100 (EGS). Despite this strong enhancement conformation modified (EGP) was not altered vaccination with EGP generated responses recognized cells expressing EGS high functional avidity. Based these promising results, p3P modification applied highly immunodominant Lymphocytic Choriomeningitis Virus gp33 associated escape variants Y4F Y4A. As for gp100, found increase MHC epitopes V3P, PA PF, while altering their structures. Accordingly, were cross-reactive between native enhanced and, when used C57BL/6 mice, PF elicited focused response against D/Y4F. In parallel, surface plasmon resonance (SPR) measurements revealed did only enhance but also directly affinity cognate receptors (TCRs). To fully characterize molecular details underlying two enhancing effects, thermostability, TCR binding dynamics (MD) D/EGP measured comparison D/EGS. Furthermore, contribution Y159, conserved tyrosine structurally juxtaposed p3P, assessed using set soluble D-Y159 variants. conclusion, clearly demonstrated specific interactions aromatic ring Y159 responsible capacity. Surprisingly, entirely independent suggesting direct buried binding. These findings underscore potential MHC-I-restricted residues, specifically indicating affinity, which could have anticipated our current understanding factors shaping recognition. Not different elicitation, induction broadly neutralizing antibodies Human Immunodeficiency type 1 (HIV-1) date still an elusive goal despite extensive characterization respective antibody-epitope interactions. One central challenges virus adapted immune pressure most relevant antibody HIV envelope proteins (Env) least immunogenic. Therefore, heterologous prime-boost strategy designed priming rabbits HIV-1 env plasmids followed by recombinant Simian (SIV) Env boost. While SIV trimers inherently favorable because higher stability, approach chosen preferentially boost few sites Env. described generally validated warrants future investigations as it lead potent though remains established if nature prime solely responsible. summary, studies presented thesis provide structural platform novel MHC-I enhancement. Additionally, immunizations offer addition existing strategies HIV.