T cell recognition of hypervariable region-1 from hepatitis C virus envelope protein with multiple class II MHC molecules in mice and humans: preferential help for induction of antibodies to the hypervariable region.
Hypervariable region-1 (HVR1) from the hepatitis C virus (HCV) envelope protein is thought to be a target for neutralizing Abs. To explore HVR1 recognition by helper T cells, and their role in Ab responses, we attempted to generate helper T cells specific for HVR1 in mice of three MHC types, and with PBMC from HCV-infected HLA-diverse humans. In both species, HVR1 was presented by >1 class II MHC molecule to CD4+ helper T cells and showed surprising interisolate cross-reactivity. The epitope for two DR4+ patients was mapped to a more conserved C-terminal sequence containing a DR4 binding motif, possibly accounting for cross-reactivity. Strikingly, Abs to patients' own HVR1 sequences were found only in patients with T cell responses to HVR1, even though all had Abs to envelope protein, suggesting that induction of Abs to HVR1 depends on helper T cells specific for a sequence proximal to the Ab epitope. Thus, helper T cells specific for HVR1 may be functionally important in inducing neutralizing Abs to HCV. These results may be the first example of "T-B reciprocity," in which proximity of a helper T cell epitope determines Ab epitope specificity, in a human disease setting.
Shirai
M
M
Department of Microbiology, Yamaguchi University School of Medicine, Japan.
Arichi
T
T
Chen
M
M
Masaki
T
T
Nishioka
M
M
Ikeda
K
K
Takahashi
H
H
Enomoto
N
N
Saito
T
T
Major
M E
ME
Nakazawa
T
T
Akatsuka
T
T
Feinstone
S M
SM
Berzofsky
J A
JA
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000956:Antigens, Viral / Q000276:immunology*; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology
D000914:Antibodies, Viral; D000956:Antigens, Viral; C087035:E1 protein, Hepatitis C virus; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus