title: HLA-DM constrains epitope selection in the human CD4 T cell response to vaccinia virus by favoring the presentation of peptides with longer HLA-DM-mediated half-lives.
abstract: HLA-DM (DM) is a nonclassical MHC class II (MHC II) protein that acts as a peptide editor to mediate the exchange of peptides loaded onto MHC II during Ag presentation. Although the ability of DM to promote peptide exchange in vitro and in vivo is well established, the role of DM in epitope selection is still unclear, especially in human response to infectious disease. In this study, we addressed this question in the context of the human CD4 T cell response to vaccinia virus. We measured the IC(50), intrinsic dissociation t(1/2), and DM-mediated dissociation t(1/2) for a large set of peptides derived from the major core protein A10L and other known vaccinia epitopes bound to HLA-DR1 and compared these properties to the presence and magnitude of peptide-specific CD4(+) T cell responses. We found that MHC II-peptide complex kinetic stability in the presence of DM distinguishes T cell epitopes from nonrecognized peptides in A10L peptides and also in a set of predicted tight binders from the entire vaccinia genome. Taken together, these analyses demonstrate that DM-mediated dissociation t(1/2) is a strong and independent factor governing peptide immunogenicity by favoring the presentation of peptides with greater kinetic stability in the presence of DM.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Liusong
authors.initials: L
authors.lastname: Yin
authors.forename: J Mauricio
authors.initials: JM
authors.lastname: Calvo-Calle
authors.forename: Omar
authors.initials: O
authors.lastname: Dominguez-Amorocho
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology*; D001667:Binding, Competitive / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006681:HLA-D Antigens / Q000737:chemistry / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D010446:Peptide Fragments; D014764:Viral Proteins