ABSTRACT
To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8(+) T cells responding to the live yellow fever virus and smallpox vaccines--two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8(+) T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8(+) T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8(+) T cells specific for persistent viruses. These results provide a benchmark for CD8(+) T cell responses induced by two of the most effective vaccines ever developed.
Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Smallpox Vaccine/immunology , T-Lymphocyte Subsets/immunology , Yellow Fever Vaccine/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Lymphocyte Activation , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Vaccination , Vaccinia virus/immunology , Yellow Fever Vaccine/metabolismABSTRACT
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.