Yellow Fever Virus 17D Envelope and NS3 Proteins Are Major Targets of the Antiviral T Cell Response in Mice

Abstract

The yellow fever virus 17D vaccine strain is one of the most effective and safe vaccines available. The immune response after immunization is characterized by long-lasting high titers of neutralizing antibodies. Here, we have initiated a characterization of YFV-17D-specific cellular immune responses. This study makes three points. First, we have identified two CD8 T cell epitopes and one CD4 T cell epitope. An H-2Kb-restricted dominant epitope was mapped in the NS3 protein, whereas the viral envelope protein harbored an H-2Db-restricted subdominant epitope and the I-Ab-restricted CD4 T cell epitope. Second, illustrating the concept of immunodomination, we found that after abrogation of the dominant response in H-2Kb knockout mice, the frequencies of T cells recognizing the subdominant Db-restricted epitope increased dramatically. Finally, the H-2Db-restricted epitope lacks the canonical Asn anchor residue at position 5, indicating that epitopes may be missed by strict application of the H-2Db-binding motif. Identification of these T cell epitopes will facilitate studies on the cellular immunity against YFV-based expression or immunization vectors.

Yellow Fever Vaccination Elicits Broad Functional CD4 + T Cell Responses That Recognize Structural and Nonstructural Proteins

“…While a broad array of epitopes were recognized by CD4 ϩ T cells, only the envelope and NS3 proteins were recognized by every subject in our study, each containing an epitope for all of the HLA-DRB1 alleles that we tested. These results agree with an earlier study in which responses in immunized mice focused on the envelope and NS3 proteins (28). However, NS1 epitopes were recognized by the highest frequencies of T cells.…”

Dominant CD8+T-Lymphocyte Responses Suppress Expansion of Vaccine-Elicited Subdominant T Lymphocytes in Rhesus Monkeys Challenged with Pathogenic Simian-Human Immunodeficiency Virus

“…In murine models, the abrogation of immunodominant epitope-specific CD8 ϩ T-lymphocyte responses has led to the enhancement of subdominant epitope-specific CD8 ϩ T-lymphocyte responses. Such enhanced responses have been shown by infection of knockout mice lacking the restricting MHC class I allele that presents the immunodominant epitope, deletion of immunodominant epitope-specific CD8 ϩ T lymphocytes in the thymus, and infection of mice with a viral variant that cannot elicit the immunodominant CD8 ϩ T-lymphocyte response (48)(49)(50). In the present study, we show an enhanced CD8 ϩ T-lymphocyte response to a subdominant SHIV epitope following challenge of vaccinated rhesus mon- ϩ rhesus monkeys were measured.…”

Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

“…In murine studies, elimination of an immunodominant epitope-specific CD8 ϩ T lymphocyte response has led to the enhancement of a subdominant epitope-specific CD8 ϩ T lymphocyte response. Such an enhancement of subdominant responses has been shown in situations where the immunodominant epitope-specific CD8 ϩ T lymphocyte response was circumvented by infecting with an immunodominant epitope-negative viral variant (20), by infecting knockout mice lacking the MHC-I molecule that presents the immunodominant epitope (21) or by deleting immunodominant epitope-specific CD8 ϩ T lymphocytes by expressing the immunodominant epitope in the thymus as a transgene (19).…”