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

• Published in: Science translational medicine 2015-04, Vol.7 (282), p.282ra48-282ra48
• Main Authors: Fuertes Marraco, Silvia A, Soneson, Charlotte, Cagnon, Laurène, Gannon, Philippe O, Allard, Mathilde, Abed Maillard, Samia, Montandon, Nicole, Rufer, Nathalie, Waldvogel, Sophie, Delorenzi, Mauro, Speiser, Daniel E
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antigens, Viral - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Epitopes - immunology; Gene Expression Profiling; Homeostasis; Humans; Immunologic Memory; Interleukin-15 - metabolism; Lymphocyte Subsets - immunology; Middle Aged; Peptides - immunology; Phenotype; RNA, Messenger - genetics; RNA, Messenger - metabolism; Vaccination; Yellow Fever - genetics; Yellow Fever - immunology; Yellow Fever - virology; Yellow Fever Vaccine - immunology; Young Adult
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aaa3700

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.