The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response

Emory Vaccine Center and the Hope Clinic, Emory University School of Medicine, Atlanta, GA 30022, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2009; 183(12):7919-30. DOI: 10.4049/jimmunol.0803903
Source: PubMed


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 down-regulate 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-gamma, TNF-alpha, IL-2, and MIP-1beta. 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.

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    • "Within an overall Th1 response, individual cells may express subsets of the Th1 cytokine pattern [8]. “Multifunctional” T cells produce a greater number of cytokines, and an increased proportion of multifunctional cells correlates with better protection against Leishmania major in mice [9], slower progression of HIV infection to AIDS [10], and protection by vaccines against yellow fever [11]–[13], and vaccinia virus [14]. However, in tuberculosis [15], multifunctional T cells correlate with increased disease. "
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    • "Polyfunctional T cells correlate better with protective immunity to viruses than do single cytokine secretors [25], [26]. This includes reports of polyfunctional T cell responses resulting from YFV 17D flaviviral vaccination [27]. To investigate the polyfunctional characteristics of T cells from WNV infected individuals, we stimulated PBMC from twelve A*11:01 infected individuals with the six WNV peptides reported here and analyzed peptide-specific induction of IFN-γ, TNF-α, IL-2, MIP-1β and CD107a (a degranulation marker) in CD8+ T lymphocytes (Figure 5). "
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    • "This transition is associated with the transition from effector memory to central memory. Reproduced with permission from [5] (copyright 2009. The American Association of Immunologists, Inc.). "
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