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 1

Identification of CD45RO–CCR7+ virus-specific CD4+ T cells after YFV vaccination.

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Identification of CD45RO–CCR7+ virus-specific CD4+ T cells after YFV vac...
(A) Direct ex vivo tetramer and antibody staining of a representative YFV tetramer+ (tet+) population using blood collected about 7 months after YFV vaccination. (B) The percentage of YFV tet+ T cells with the indicated combination of CD45RO and CCR7 expression. Plot summarizes data from 36 specificities 7 to 34 months after YFV vaccination from 7 donors. (C and D) The abundance of CD45RO–CCR7+YFV tet+ CD4+ T cells in 7 healthy participants was quantified as a percentage of tetramer+ cells (C) or by frequency (D). Each symbol represents data from a distinct YFV-specific population. Experiments were repeated an average of 3.3 times. (E) The correlation between CD45RO–CCR7+YFV tet+ T cell frequency and the overall tet+ frequency of the same population at least 7 months after vaccination. (F) The correlation between the CD45RO–CCR7+YFV tet+ T cell frequency and the fold-change from the pre-vaccine baseline to the memory time point. CD45RO–CCR7+tet+ frequencies were determined using samples taken 7 to 34 months after vaccination. n = 33, and populations with no post-vaccine naive cells were excluded. Repeated measures (RM) 1-way ANOVA (B) or mixed effects analysis (C and D) was performed and corrected with Tukey’s multiple comparisons test. (E and F) Pearson’s correlation was computed. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.