Epitope-Specific Regulation of Memory Programming by Differential Duration of Antigen Presentation to Influenza-Specific CD8+ T Cells

Memory CD8+ T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8+ T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8+ T cells encountered antigen on CD40-licensed, CD70-expressing, CD103−CD11bhi dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-γ (IFN-γ)-producing ability. In contrast, polymerase (PA)-specific CD8+ T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8+ T cells with strong proliferative and cytokine-producing ability. As a result, CD8+ T cells responding to abundant antigens, like NP, dominated the secondary response. •NP-specific and PA-specific CD8+ T cells differentially require CD40, CD25, and CD27•Presentation of NP is sustained for longer than 6 days, but presentation of PA is not•CD40 is necessary on DCs for cross-priming and late NP presentation•CD40-mediated late antigen-presentation maintains CD25 and CD27 on T cells The functional properties of memory CD8+ T cells are programmed during the primary response. Ballesteros-Tato et al. show that T cells responding to different epitopes of influenza virus receive different programming signals depending on the duration of antigen presentation.