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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

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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 5

TMN cells are clonally related to effector T cells and contribute to the maintenance of the naive repertoire after vaccination.

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TMN cells are clonally related to effector T cells and contribute to the...
(A) The number of TCRs from YF45 tet+ T cells from the indicated donors, before and 14 days after YFV vaccination. (B) TCRs from cells in A were compared to TMN-derived TCRs in the day 210–242 post-vaccine samples. Bar graphs show the percentages of cells with or without a match. (C) Each circos plot represents TCRs from TMN YF45 tet+ cells and TCRs from the same specificities, before and 14 days after YFV vaccination, from the same donors. Cells are ordered by frequency within each arc. Gray marks cells expressing unique TCRs; other colors represent expanded or shared sequences. Connecting lines highlight shared TCRs between a TMN cell and cells in a previous time point. (D) The number and phenotypes of T cells in the day 14 sample that matched a TMN-derived clonotype from the memory time point. (E) Clonal dynamics of a TCR expressed by a TMN cell in the 14-day post-vaccine sample. Plot shows the number and phenotypes of T cells that expressed the same TCR sequence at the indicated time points. ND, not detected. (F and G) The frequencies of CD45RO–CCR7+ YFV-specific T cells before and after vaccination for the corresponding populations (F). Post-vaccine CD45RO–CCR7+tet+ cells were separated into TSCM or TMN subsets based on CXCR3, CD95, CD11a, or CD49d staining (G). (H) Plot compares the frequencies of CD45RO–CCR7+tet+ cells before vaccination with the frequencies of TMN cells in the corresponding population from the post-vaccine sample. (I) The post-vaccine TMN frequency of each tet+ population was divided by its initial CD45RO–CCR7+ frequency before vaccination. The ratio is defined as a gain if above 1 and a loss if below 1. Pie chart shows the numbers of populations that had gained or lost naive T cells after vaccination. (J) Plot shows the fold-change in tet+ frequency, from the pre-vaccine baseline to the memory time point, for populations that had gained or lost naive cells. For F, H, and J, n = 27 tetramer+ populations. Welch’s t test was performed. *P < 0.05, **P < 0.01.

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