Preservation of naive-phenotype CD4+ T cells after vaccination contributes to durable immunity
Yi-Gen Pan, Laurent Bartolo, Ruozhang Xu, Bijal V. Patel, Veronika I. Zarnitsyna, Laura F. Su
Yi-Gen Pan, Laurent Bartolo, Ruozhang Xu, Bijal V. Patel, Veronika I. Zarnitsyna, Laura F. Su
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Research Article Immunology Vaccines

Preservation of naive-phenotype CD4+ T cells after vaccination contributes to durable immunity

Abstract

Memory T cells are conventionally associated with durable recall responses. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found CD45RO–CCR7+ virus-specific CD4+ T cells that expanded shortly after vaccination and persisted months to years after immunization. Further phenotypic analyses revealed the presence of stem cell–like memory T cells within this subset. In addition, after vaccination T cells lacking known memory markers and functionally resembling genuine naive T cells were identified, referred to herein as marker-negative T (TMN) cells. Single-cell TCR sequencing detected expanded clonotypes within the TMN subset and identified TMN TCRs shared with memory and effector T cells. Longitudinal tracking of YFV-specific responses over subsequent years revealed superior stability of TMN cells, which correlated with the longevity of the overall tetramer+ population. These findings uncover additional complexity within the post-immune T cell compartment and implicate TMN cells in durable immune responses.

Authors

Yi-Gen Pan, Laurent Bartolo, Ruozhang Xu, Bijal V. Patel, Veronika I. Zarnitsyna, Laura F. Su

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Figure 2

Post-vaccine CD4+ T cells are heterogeneous and include naive-like subsets.

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Post-vaccine CD4+ T cells are heterogeneous and include naive-like subse...
(A) FACS plots show the expression of the indicated marker on a representative YFV-specific population. The tet+ population is overlaid onto tet– bulk CD4+ T cells. (B) UMAP displays phenograph-defined clusters. Data combine 1,465 CD4+ cells labeled by 7 YFV tetramers from HD3. (C and D) The staining intensity of individual markers is shown on a heatmap for each cluster (C) or displayed on the UMAP (D). (E and F) The relative abundance of CD45RO–CCR7+ YFV-specific T cells by the indicated numbers of markers (E) or the type of markers (F). Frequency in F combines all cells positive for a particular marker within the CD45RO–CCR7+ subset. Marker combinations were determined using Boolean operators on manually defined gates. Each symbol represents a tetramer+ population (n = 28). Experiments were repeated an average of 2.5 times. (G) PBMCs were stimulated for 4–5 hours by PMA and ionomycin and assayed for cytokine production by intracellular cytokine staining. The plot shows representative TNF-α and IFN-γ expression by TMN cells and memory T cells (non-CD45RO–CD28+) from the same tetramer-labeled population. (H) T cell responses by TNF-α and IFN-γ production for the indicated phenotypic subset. Each population was identified with a pool of 5–7 tetramers of the same DR allele, using cells from 3 donors. (E and F) RM 1-way ANOVA was performed and corrected with Tukey’s multiple comparison test. (H) The Friedman test was performed and corrected using Dunn’s multiple comparison test. *P < 0.05, ***P < 0.001, ****P < 0.0001.