Role of APC in the selection of immunodominant T cell epitopes.
Following antigenic challenge, MHC-restricted T cell responses are directed against a few dominant antigenic epitopes. Here, evidence is provided demonstrating the importance of APC in modulating the hierarchy of MHC class II-restricted T cell responses. Biochemical analysis of class II:peptide complexes in B cells revealed the presentation of a hierarchy of peptides derived from the Ig self Ag. Functional studies of kappa peptide:class II complexes from these cells indicated that nearly 20-fold more of an immunodominant epitope derived from kappa L chains was bound to class II DR4 compared with a subdominant epitope from this same Ag. In vivo, T cell responses were preferentially directed against the dominant kappa epitope as shown using Ig-primed DR4 transgenic mice. The bias in kappa epitope presentation was not linked to differences in class II:kappa peptide-binding affinity or epitope editing by HLA-DM. Rather, changes in native Ag structure were found to disrupt presentation of the immunodominant but not the subdominant kappa epitope; Ag refolding restored kappa epitope presentation. Thus, Ag tertiary conformation along with processing reactions within APC contribute to the selective presentation of a hierarchy of epitopes by MHC class II molecules.
Ma
C
C
Department of Microbiology and Immunology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis 46202, USA.
Whiteley
P E
PE
Cameron
P M
PM
Freed
D C
DC
Pressey
A
A
Chen
S L
SL
Garni-Wagner
B
B
Fang
C
C
Zaller
D M
DM
Wicker
L S
LS
Blum
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D006680:HLA Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive; D016056:Immunodominant Epitopes / Q000378:metabolism*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology / Q000378:metabolism; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D007136:Immunoglobulins; D010455:Peptides