Research ArticleInfectious Disease

Long-lasting stem cell–like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ra48
DOI: 10.1126/scitranslmed.aaa3700

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Yellow fever vaccine induces long-term naïve-like memory

In the ongoing quest to find better models of human disease, humans themselves are frequently overlooked. New vaccines for viral infections have hit barriers in translating attempts to induce protective immunity by producing long-lasting memory T cell responses. Now, Fuertes Marraco et al. report that individuals who receive the current yellow fever vaccine develop just that. They found that yellow fever–specific CD8+ T cells with a naïve-like phenotype persisted in vaccinated individuals for more than 25 years. These cells were capable of self-renewal and resembled the stem cell–like memory subset. Thus, by studying vaccinated individuals and building on their own success, researcher may learn—in people—what exactly makes long-term memory T cells tick.


Efficient and persisting immune memory is essential for long-term protection from infectious and malignant diseases. The yellow fever (YF) vaccine is a live attenuated virus that mediates lifelong protection, with recent studies showing that the CD8+ T cell response is particularly robust. Yet, limited data exist regarding the long-term CD8+ T cell response, with no studies beyond 5 years after vaccination. We investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-specific CD8+ T cells were readily detected in almost all donors (38 of 41), with frequencies decreasing with time. As previously described, effector cells dominated the response early after vaccination. We detected a population of naïve-like YF-specific CD8+ T cells that was stably maintained for more than 25 years and was capable of self-renewal ex vivo. In-depth analyses of markers and genome-wide mRNA profiling showed that naïve-like YF-specific CD8+ T cells in vaccinees (i) were distinct from genuine naïve cells in unvaccinated donors, (ii) resembled the recently described stem cell–like memory subset (Tscm), and (iii) among all differentiated subsets, had profiles closest to naïve cells. Our findings reveal that CD8+ Tscm are efficiently induced by a vaccine in humans, persist for decades, and preserve a naïveness-like profile. These data support YF vaccination as an optimal mechanistic model for the study of long-lasting memory CD8+ T cells in humans.

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