Effector and Central Memory Poly-Functional CD4+ and CD8+ T Cells are Boosted upon ZOSTAVAX® Vaccination

摘要

ZOSTAVAX^® is a live attenuated varicella-zoster virus (VZV) vaccine that is licensed for the protection of individuals ≥50 years against shingles and its most common complication, postherpetic neuralgia. While IFNγ responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4⁺ and CD8⁺ T cell responses induced 3–4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4⁺ T cells were poly-functional CD154⁺IFNγ⁺IL-2⁺TNFα⁺ cells, which were boosted upon vaccination. The CD4⁺ T cells were broadly reactive to several VZV proteins, with immediate early (IE) 63 ranking the highest among them in the fold rise of poly-functional cells, followed by IE62, gB, open reading frame (ORF) 9, and gE. We identified a novel poly-functional ORF9-specific CD8⁺ T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4⁺ and CD8⁺ T cells produced significantly higher levels of IFNγ, IL-2, and TNFα compared to mono-functional cells. After vaccination, a boost in the expression of IFNγ by poly-functional IE63- and ORF9-specific CD4⁺ T cells and IFNγ, IL-2, and TNFα by ORF9-specific poly-functional CD8⁺ T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7⁻CD45RA⁻CD45RO⁺), and central (CCR7⁺CD45RA⁻CD45RO⁺) memory phenotypes, which expressed comparable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4⁺ T cells and ORF9-specific CD8⁺ T cells may contribute toward ZOSTAVAX efficacy.