Clustering of Th cell epitopes on exposed regions of HIV envelope despite defects in antibody activity.
A long-standing question in the field of immunology concerns the factors that contribute to Th cell epitope immunodominance. For a number of viral membrane proteins, Th cell epitopes are localized to exposed protein surfaces, often overlapping with Ab binding sites. It has therefore been proposed that Abs on B cell surfaces selectively bind and protect exposed protein fragments during Ag processing, and that this interaction helps to shape the Th cell repertoire. While attractive in concept, this hypothesis has not been thoroughly tested. To test this hypothesis, we have compared Th cell peptide immunodominance in normal C57BL/6 mice with that in C57BL/6( micro MT/ micro MT) mice (lacking normal B cell activity). Animals were first vaccinated with DNA constructs expressing one of three different HIV envelope proteins, after which the CD4(+) T cell response profiles were characterized toward overlapping peptides using an IFN-gamma ELISPOT assay. We found a striking similarity between the peptide response profiles in the two mouse strains. Profiles also matched those of previous experiments in which different envelope vaccination regimens were used. Our results clearly demonstrate that normal Ab activity is not required for the establishment or maintenance of Th peptide immunodominance in the HIV envelope response. To explain the clustering of Th cell epitopes, we propose that localization of peptide on exposed envelope surfaces facilitates proteolytic activity and preferential peptide shuttling through the Ag processing pathway.
Brown
Scott A
SA
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Stambas
John
J
Zhan
Xiaoyan
X
Slobod
Karen S
KS
Coleclough
Chris
C
Zirkel
Amy
A
Surman
Sherri
S
White
Stephen W
SW
Doherty
Peter C
PC
Hurwitz
Julia L
JL
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015686:Gene Products, env / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D015483:HIV Antibodies / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015686:Gene Products, env; D015483:HIV Antibodies; D016056:Immunodominant Epitopes