Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where
yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by
neutralizing antibodies and strong T cell responses. This
vaccine provides an excellent model for studying human immunity. While several studies have characterized YFV-specific antibody and CD8(+) T cell responses, less is known about YFV-specific CD4(+) T cells. Here we characterize the
epitope specificity, functional attributes, and dynamics of YFV-specific T cell responses in vaccinated subjects by investigating peripheral blood mononuclear cells by using
HLA-DR tetramers. A total of 112
epitopes restricted by seven common
HLA-DRB1 alleles were identified.
Epitopes were present within all YFV
proteins, but the capsid, envelope, NS2a, and NS3
proteins had the highest
epitope density. Antibody blocking demonstrated that the majority of YFV-specific T cells were
HLA-DR restricted. Therefore, CD4(+) T cell responses could be effectively characterized with
HLA-DR tetramers. Ex vivo tetramer analysis revealed that YFV-specific T cells persisted at frequencies ranging from 0 to 100 cells per million that are detectable years after vaccination. Longitudinal analysis indicated that YFV-specific CD4(+) T cells reached peak frequencies, often exceeding 250 cells per million, approximately 2 weeks after vaccination. As frequencies subsequently declined, YFV-specific cells regained CCR7 expression, indicating a shift from effector to central memory. Cells were typically CXCR3 positive, suggesting Th1 polarization, and produced
gamma interferon and other
cytokines after reactivation in vitro. Therefore, YFV elicits robust early effector CD4(+) T cell responses that contract, forming a detectable memory population.