Abstract
The CD8+ Tcell response to an antigen is composed of many Tcell clones with unique Tcell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual Tcell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8+ Tcell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8+ Tcell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human Tcell response to acute viral infections.
Highlights
Primary adaptive immune responses lead to clonal expansion of rare antigen-specific naive CD8+ T cells and generation of longlived memory cells, which guard against subsequent infections (Kaech and Ahmed, 2001)
We show that the heterogeneity of primary yellow fever virus (YFV)-specific human memory CD8+ T cells is created by the sum of distinct clonal T cell identities along a continuum from TSCM to TEMRA
We demonstrate that secondary CD8+ T cell responses are clonally biased, with distinct effector progeny generated from CD8+ TSCM and TEMRA founder cells
Summary
Primary adaptive immune responses lead to clonal expansion of rare antigen-specific naive CD8+ T cells and generation of longlived memory cells, which guard against subsequent infections (Kaech and Ahmed, 2001). During this response, CD8+ T cells differentiate into a diverse array of effector and memory cells that exhibit distinct phenotypic and functional properties (Champagne et al, 2001; Gillespie et al, 2000; Jameson and Masopust, 2009, 2018; Sallusto et al, 1999; Willinger et al, 2005). TEM have been shown to be more protective than TCM against reinfection with vaccinia virus, despite being less protective than TCM against lymphocytic choriomeningitis virus (LCMV) infection in adoptive transfer models (Bachmann et al, 2005), suggesting that the protective roles of these subsets are context-dependent
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