Identification of an H-2Db-restricted CD8+ cytotoxic T lymphocyte epitope in the matrix protein of respiratory syncytial virus

Abstract

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-2d-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 187-195 (NAITNAKII). 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-2b-restricted CTL epitope provides access to genetically modified H-2b mice for more detailed studies of CTL mechanisms in RSV infection.

IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus

“…The leukocytes recovered in the pellet were washed and cultured in RPMI 1640 medium in the presence of ultraviolet light (UV)-inactivated RSV or an immunodominant H-2 brestricted epitope (M 187-195 ) from the RSV M protein (22). Culture supernatants were harvested after 4 days of culture and used for assessment of IFN-g production by ELISA.…”

Overcoming T-Cell-Mediated Immunopathology to Achieve Safe Respiratory Syncytial Virus Vaccination

“…In contrast to immunization with FI-RSV, vacvG, or vacvF, RSV challenge of BALB/c mice immunized with vacvM2 elicits a memory CD8 T cell response in the absence of a detectable memory CD4 T cell response [25,57,58]. Mice co-immunized with vacvG and vacvM2 do not develop pulmonary eosinophilia upon RSV challenge demonstrating a protective role for M2-specific memory CD8 T cells [24,59].…”

“…Therefore, these data suggest that wild-type mice previously immunized with vacvF do not develop pulmonary eosinophilia after RSV challenge due to the inhibition of the RSV-specific memory Th2 response by IFN-γ produced by F-specific memory CD8 T cells. M2-specific memory CD8 T cells can also produce IFN-γ [24,57,59]. However, in contrast to vacvFimmunized mice, M2-specific memory CD8 T cell inhibition of pulmonary eosinophilia does not require IFN-γ [24].…”

“…Since there is no detectable memory CD4 T cell response to the M2 protein, this indicates a direct role for memory CD8 T cells in mediating weight loss [25,57,58]. Thus, memory CD8 T cell responses, although capable of preventing the development of pulmonary eosinophilia, can induce systemic immunopathology during secondary RSV infections.…”

Major Histocompatibility Complex-Dependent Cytotoxic T Lymphocyte Repertoire and Functional Avidity Contribute to Strain-Specific Disease Susceptibility after Murine Respiratory Syncytial Virus Infection

“…To further investigate the T cell repertoire in the different mouse strains, we analyzed defined virus-derived CTL responses. After RSV infection of BALB/c mice, the majority of the RSV-specific CTL response is directed against the immunodominant CTL epitope M2-1 82-90 (M2-1 82), presented by H-2K d (29,30), while in C57BL/6 mice, the immunodominant epitope is M187-195 (M187), presented by H-2D b (48). On d7 after RSV infection, in BALB/c and C57BL/6-H-2 d mice, about 20% of the pulmonary CTL produced IFN-␥ in response to M2-1 82 stimulation (Fig.…”