Identification of a Common HLA-DP4-Restricted T-Cell Epitope in the Conserved Region of the Respiratory Syncytial Virus G Protein (original) (raw)
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Characterization of Respiratory Syncytial Virus M- and M2-Specific CD4 T Cells in a Murine Model
Journal of Virology, 2009
CD4 T cells have been shown to play an important role in the immunity and immunopathogenesis of respiratory syncytial virus (RSV) infection. We identified two novel CD4 T-cell epitopes in the RSV M and M2 proteins with core sequences M 213-223 (FKYIKPQSQFI) and M2 27-37 (YFEWPPHALLV). Peptides containing the epitopes stimulated RSV-specific CD4 T cells to produce gamma interferon (IFN-γ), interleukin 2 (IL-2), and other Th1- and Th2-type cytokines in an I-A b -restricted pattern. Construction of fluorochrome-conjugated peptide-I-A b class II tetramers revealed RSV M- and M2-specific CD4 T-cell responses in RSV-infected mice in a hierarchical pattern. Peptide-activated CD4 T cells from lungs were more activated and differentiated, and had greater IFN-γ expression, than CD4 T cells from the spleen, which, in contrast, produced greater levels of IL-2. In addition, M 209-223 peptide-activated CD4 T cells reduced IFN-γ and IL-2 production in M- and M2-specific CD8 T-cell responses to D b...
HLA-DP4 presents an immunodominant peptide from the RSV G protein to CD4 T cells
Virology, 2004
CD4 T cells play a crucial role during virus infections by producing antiviral cytokines and by regulating humoral and cellular immune responses. Unfortunately however, exaggerated CD4 T cell responses can cause significant immune-mediated disease as was observed during RSV infections in children previously vaccinated with a formalin-inactivated virus in the 1960s. It has been observed that vaccination with the G protein of RSV tends to prime mice for a similar Th2-mediated enhanced disease. Whether the G protein may play a role in enhanced disease in man is unclear. In the present study, we identified an immunodominant epitope in the conserved region of the G protein encompassing amino acid residues 162-175. This epitope is presented in the context of HLA-DPB1*0401 and DPB1*0402, the most prevalent HLA class II alleles. Importantly, in some patients, a mixed Th1/Th2 response against this epitope was found in bronchoalveolar lavage samples during primary RSV infections.
Journal of Virology, 2003
Memory CD4 T-cell responses against respiratory syncytial virus (RSV) were evaluated in peripheral blood mononuclear cells of healthy blood donors with gamma interferon enzyme-linked immunospot (Elispot) assays. RSV-specific responses were detected in every donor at levels varying between 0.05 and 0.3% of CD4 T cells. For all donors tested, a considerable component of the CD4 T-cell response was directed against the fusion (F) protein of RSV. We characterized a set of 31 immunodominant antigenic peptides targeted by CD4 T cells in the context of the most prevalent HLA class II molecules within the Caucasian population. Most antigenic peptides were HLA-DR restricted, whereas two dominant DQ peptides were also identified. The antigenic peptides identified were located across the entire sequence of the F protein. Several peptides were presented by more than one major histocompatibility complex class II molecule. Furthermore, most donors recognized several F peptides. Detailed knowledge about immunodominant antigenic peptides will facilitate the ability to monitor CD4 T-cell responses in patients and the measurement of correlates of protection in vaccinated subjects.
J Virol, 2000
We analyzed the protective mechanisms induced against respiratory syncytial virus subgroup A (RSV-A) infection in the lower and upper respiratory tracts (LRT and URT) of BALB/c mice after intraperitoneal immunization with a recombinant fusion protein incorporating residues 130 to 230 of RSV-A G protein (BBG2Na). Mother-to-offspring antibody (Ab) transfer and adoptive transfer of BBG2Na-primed B cells into SCID mice demonstrated that Abs are important for LRT protection but have no effect on URT infection. In contrast, RSV-A clearance in the URT was achieved in a dose-dependent fashion after adoptive transfer of BBG2Na-primed T cells, while it was abolished in BBG2Na-immunized mice upon in vivo depletion of CD4 ؉ , but not CD8 ؉ , T cells. Furthermore, the conserved RSV-A G protein cysteines and residues 193 and 194, overlapping the recently identified T helper cell epitope on the G protein (P. W. Tebbey et al., J. Exp. Med. 188:1967-1972, 1998), were found to be essential for URT but not LRT protection. Taken together, these results demonstrate for the first time that CD4 ؉ T cells induced upon parenteral immunization with an RSV G protein fragment play a critical role in URT protection of normal mice against RSV infection.
Helper T Cell Recognition of Respiratory Syncytial Virus in Mice
Journal of General Virology, 1988
In this study we aimed to define the protein and viral subtype specificities of helper Th cells to respiratory syncytial virus (RSV). BALB/c mice were primed by infection with RSV, or with vaccinia viruses (VV) containing genes encoding several individual RSV proteins. Priming for Th cell memory was assayed by stimulating spleen cells in vitro with different RSV isolates and measuring RSV-specific interleukin 2 (IL-2) release by T cells into supernatants using an IL-2-dependent CTLL cell, line. Splenocytes from mice primed intranasally with RSV exhibited RSV-specific Th cell memory, whereas those from unprimed mice did not. Th cell recognition was in part specific to the strain of RSV used in priming and in part cross-reactive between RSV strains. Intraperitoneal priming with RSV fusion protein-expressing VV or nucleoprotein-expressing VV induced a stronger RSV-specific Th cell response than the attachment glycoprotein-expressing VV which produced only slight Th recognition. No Th cell recognition of two non-structural proteins (1A and 1 B) could be demonstrated.
Virology, 2005
Cytotoxic T lymphocytes (CTL) play a significant role in the clearance of respiratory syncytial virus (RSV) infection in humans and mice. Identification of class I MHC-restricted CTL epitopes is critical in elucidating mechanisms of CTL responses against viral infections. However, only four H-2 d -restricted epitopes have been reported in mice. Because of the diversity of transgenic and knockout mice available to study immune responses, new epitopes in additional strains of mice must be identified. We therefore attempted to discover novel CTL epitopes in C57Bl/6 mice. Our efforts revealed a new H-2D b -restricted CTL epitope from the RSV M protein, corresponding to aa [187][188][189][190][191][192][193][194][195]. Also, M187 -195-specific CTLs were activated with kinetics similar to the immunodominant BALB/c epitope, M2 82 -90. This is the first RSV-specific CTL epitope described in a strain of mice other than BALB/c. Furthermore, identification of this H-2 b -restricted CTL epitope provides access to genetically modified H-2 b mice for more detailed studies of CTL mechanisms in RSV infection. Published by Elsevier Inc.
Vaccine, 2008
Cytotoxic T lymphocytes are critical for the control of respiratory syncytial virus infection in humans and mice. Recently, we identified a new H-2K d restricted subdominant epitope in the RSV M2 protein. In this study, we investigated if modification of anchor residues at positions 2 and 9 in the dominant M2 82-90 epitope in the M2 protein would alter the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 proteins. We showed that immunogenicity of the subdominant epitope M2 127-135 was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to the subdominant epitope.