The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8⁺ T cell response

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8⁺ T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8⁺ T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8⁺ T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8⁺ T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8⁺ T cells appear to pass through an effector phase and then gradually downregulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-γ, TNF-α, IL-2, and MIP-1β. 4) The YF-17D-specific memory CD8⁺ T cells had a phenotype (CCR7^-CD45RA⁺) that is typically associated with terminally differentiated cells with limited proliferative capacity (T _EMRA). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8⁺ T cells generated after acute viral infections.