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 3

TMN-derived T cell clones respond to antigen stimulation.

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TMN-derived T cell clones respond to antigen stimulation. (A) Schematics...
(A) Schematics of single-cell T cell cloning. Post-vaccine T cells from HD2 and HD3 were stained with 1501-YF45 tetramers; sorted based on TMN, TSCM, or TCM phenotypes; and expanded for 2 to 3 weeks in culture. (B) In vitro–expanded T cell clones were restained with tetramers and cultured with vehicle- (DMSO) or peptide-treated monocyte-derived DCs. Representative plots show tetramer staining and cytokine production by intracellular cytokine staining. (C and D) T cell clones were stimulated with decreasing concentrations of YFV peptides. The response was measured by TNF-α production (C) and quantified by EC50 values after subtracting the background signal from vehicle-treated control (D). (E) Peptide dose response of T cell clones by IFN-γ, IL-2, and IL-2+TNF-α+IFN-γ+ production. (F) Representative histograms show CTV dilution in response to 10 μg/mL of peptide stimulation. (G) Plot summarizes the frequency of the CTVlo population after a 5-day culture for clones in each phenotypic group. All experiments were repeated at least twice with n = 5 in each group. (C and E) RM 2-way ANOVA was performed and corrected with Tukey’s multiple comparison test. (D and G) Kruskal-Wallis test and Dunn’s multiple comparison test were used. PHA, phytohemagglutinin.