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 4

TMN cells are clonally related to memory T cells.

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TMN cells are clonally related to memory T cells. (A) The plot summarize...
(A) The plot summarizes the number of cells sequenced from the indicated specificities and donors collected 242 (HD2) or 210 (HD3) days after primary YFV vaccination. (B) Clone size and phenotypic distribution of YFV tet+ populations in A. Phenotypic data were obtained by index sorting: TMN (CD45RO–CCR7+CXCR3–CD95–CD11a–CD49d–), TSCM (CD45RO–CCR7+ and positive for at least 1 of CXCR3, CD95, CD11a, or CD49d), TCM (CD45RO+CCR7+), TEM (CD45RO+CCR7–), TEMRA (CD45RO–CCR7–). Cells with ambiguous phenotypes were excluded. (C) Distribution of phenotypes in B by clonotype frequency, ranked from largest to unique clonotypes. (D) The frequencies of YF45-specific T cells before vaccination and at the indicated days following YFV immunization. (E) Each circos plot represents TCRs from YF45 tet+ cells obtained 210–242 days after vaccination, separated by the associated indexed phenotypes. Cells are ordered by frequency within each arc. Gray marks cells expressing unique TCRs; other colors represent expanded or shared sequences. Shared TCRβ or TCRα and β, when a TCRα is available, is connected by a line across distinct phenotypic subsets. Blue lines highlight TCRs from TMN cells that are shared with cells expressing other phenotypes. (F) The percentage of TCRs in each memory subset that matched TMN-derived sequences. TEM, effector memory; TEMRA, effector memory cells reexpressing CD45RA.