Control of vaccinia virus skin lesions by long-term-maintained IFN-γ+TNF-α+ effector/memory CD4+ lymphocytes in humans
Bénédicte Puissant-Lubrano, … , Brigitte Autran, Behazine Combadière
Bénédicte Puissant-Lubrano, … , Brigitte Autran, Behazine Combadière
Published April 1, 2010
Citation Information: J Clin Invest. 2010;120(5):1636-1644. https://doi.org/10.1172/JCI38506.
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Research Article

Control of vaccinia virus skin lesions by long-term-maintained IFN-γ+TNF-α+ effector/memory CD4+ lymphocytes in humans

Abstract

Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-γ+TNF-α+ or IFN-γ+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination.

Authors

Bénédicte Puissant-Lubrano, Philippe Bossi, Frederick Gay, Jean-Marc Crance, Olivia Bonduelle, Daniel Garin, François Bricaire, Brigitte Autran, Behazine Combadière

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Figure 5

Residual IFN-γ+TNF-α+ long-term effector/memory CD4 lymphocytes control VV skin lesion formation after viral challenge in humans.

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Residual IFN-γ+TNF-α+ long-term effector/memory CD4 lymphocytes control ...
(A and B) PBMCs from previously vaccinated volunteers were stimulated for 16 hours with VV and harvested for flow cytometric intracellular cytokine staining. Boolean gating using FlowJo software was performed to calculate single producers, double producers, and triple producers cells in regard to IFN-γ+, IL-2+, and/or TNF-α+ as indicated. Pie chart analyses are shown for CD3+CD4+ (A) and CD3+CD8+ cells (B). Mean of percentages for each sub-population of VV-specific T cells that produce cytokines are indicated in the pie chart for 23 volunteers tested at W0 (prior to vaccination). (C and D) Dot plot representation of correlation between the size of skin lesions at day 8 after vaccination and residual VV-specific T cell responses prior to revaccination: percentage of residual VV-specific effector T cells as shown by IFN-γ+TNF-α+ or IFN-γ+IL-2+ CD3+CD4+ (C) or CD8+CD3+ (D) lymphocytes are shown. All data are shown (n = 23). Each symbol represents data from 1 individual. Statistical analyses were performed using the Spearman test.