Abstract
BackgroundMemory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion.Methodology/Principal FindingsIn the present study, naïve TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNγ, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool.Conclusions/SignificanceOur results show that naïve CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications for vaccine design.
Highlights
The generation of memory T cells is a crucial process for developing novel ways to prevent viral infections and certain forms of cancer [1,2,3]
We demonstrate that the timing at which naıve MHC class-I restricted, LCMV-specific, T cell receptor (TCR) transgenic (Tg) P14 T cell enter the primary immune response to LCMV can affect their expansion and capacity to differentiate into memory T cells
We reasoned that cells that were transferred later post infection would have less opportunity to encounter viral antigen in vivo, because LCMV antigenic load usually peaks 2–3 days after infection and virus is cleared by day 7 from most organs it shows tropism [36,37]
Summary
The generation of memory T cells is a crucial process for developing novel ways to prevent viral infections and certain forms of cancer [1,2,3]. What determines EM versus CM and how the timing of viral infection affects this differentiation process are still open questions in the field. It is not known whether naıve T cells activated at the peak viral load during antigen abundance, versus peak viral clearance when the antigen load is low, have different capacities for T cell memory formation. Costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response affecting CD8 T cell activation and memory conversion
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