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Subsequently, cathepsin cleaves them outside the HLA-II binding groove to generate the free peptides that now bind to the HLA-II allotype before forming the TCR-pHLA-II complex. Complementing this pathway is the “bind first, cut later” model, wherein epitopes are first scanned within the entire length of the antigenic protein by HLA-II allomorphs. (7,8) Consequently, this region on the peptide is termed as the binding core. Furthermore, they also dictate the binding preference of the TCR-pHLA-II ternary complex. (6) However, anchoring residues within the binding pocket of the antigen binding cleft typically interact with the 9-mer region of the peptide. (5) Furthermore, the open-ended antigen binding clefts of the heterodimeric HLA-II molecule enable peptides with size of 10- to 25-mer to form the pHLA-II. (4) This complex migrates toward the extracellular membrane to further present and interact with the T-cell receptor (TCR) displayed on the CD4 T cells. Through a process of peptide exchange, the epitope exhibiting efficacy is able to displace the endogenous class-II-associated invariant chain peptide (CLIP) to form an HLA-II and peptide complex (pHLA-II) dictated by the hydrogen bonds and noncovalent interactions between them. (2,3) The final stage in the functional maturation of HLA-II begins inside the endosome, which now has multiple antigenic peptides competing to present on the polymorphic antigen binding cleft of HLA-II allomorphs. The endosome then enters a vesicular pathway to form a lyso-endosomal complex, within which the internalized components are degraded via the acidic and proteolytic activity of lysosomes, which typically have a pH of 4.5 to 5. During the “cut first, bind later” model, (1) HLA-II-mediated antigenic processing and presentation begins by internalization of deleterious proteins, transformed cellular contents, or pathogens by phagocytosis into a cellular organelle, the endosome.
#INTREPID NATION DECIPHER CHAT PROFESSIONAL#
The CD4 T-cell response is initiated by the presentation of peptides in context with human leukocyte antigen II (HLA-II), expressed on the surface of professional antigen presenting cells (APCs). This strategy may accurately predict the peptide epitopes and thus aid in designing successful peptide vaccines. Finally, we discuss a structure-guided approach to decipher potential HLA-II binders within an antigenic protein. Furthermore, we mimic the peptide exchange mechanism and demonstrate the structural implication of an acidic environment on HLA-II binders. The present study is an attempt to understand the structural aspects of HLA-II binders by analyzing the Protein Data Bank (PDB) complexes of pHLA-II. However, the availability of structure-based epitope prediction algorithms is inadequate compared with sequence-based prediction methods. Structural analysis and understanding of the cognate peptide and HLA-II interactions are essential to empirically derive a successful peptide vaccine. The available in silico predictors of human leukocyte antigen II (HLA-II) binding peptides are sequence-based techniques, which ostensibly have balanced sensitivity and specificity.
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CD4 T-cell-based peptide vaccines involve immunization with antigenic determinants from pathogens or neoplastic cells that possess the ability to elicit a robust T helper cell response, which subsequently activates other arms of the immune system. Clinical trials indicate the gaining impetus of peptide vaccines against diseases for which an effective treatment still remains obscure. Vaccines remain the most efficacious means to avoid and eliminate morbid diseases associated with high morbidity and mortality.
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