Antigen Persistence Is Required for Dendritic Cell Licensing and CD8+ T Cell Cross-Priming

Abstract

It has been demonstrated that CD4+ T cells require Ag persistence to achieve effective priming, whereas CD8+ T cells are on “autopilot” after only a brief exposure. This finding presents a disturbing conundrum as it does not account for situations in which CD8+ T cells require CD4+ T cell help. We used a physiologic in vivo model to study the requirement of Ag persistence for the cross-priming of minor histocompatibility Ag-specific CD8+ T cells. We report inefficient cross-priming in situations in which male cells are rapidly cleared. Strikingly, the failure to achieve robust CD8+ T cell activation is not due to a problem with cross-presentation. In fact, by providing “extra help” in the form of dendritic cells (DCs) loaded with MHC class II peptide, it was possible to achieve robust activation of CD8+ T cells. Our data suggest that the “licensing” of cross-presenting DCs does not occur during their initial encounter with CD4+ T cells, thus accounting for the requirement for Ag persistence and suggesting that DCs make multiple interactions with CD8+ T cells during the priming phase. These findings imply that long-lived Ag is critical for efficient vaccination protocols in which the CD8+ T cell response is helper-dependent.

Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells

“…As compared to re-stimulation of memory cells, which may occur during a 24-36 h time course, the requirements for crosspriming naive CD8 þ T cells are more stringent and in some cases require persistent antigen and innate immune activation. [29][30][31] To evaluate the ability to prime naive T cells, we used an in vivo mouse model, injecting dying influenza-infected WT or Bax/Bak À/À MEFs by an intradermal (i.d.) route into C57BL/6 mice (H-2 b ).…”

NK cell–mediated killing of target cells triggers robust antigen-specific T cell–mediated and humoral responses

“…A recent report suggested that NK cellmediated clearance of ␤ 2 -microglobulin-deficient male cells in female recipient mice reduced H-Y-specific CD4 ϩ and CD8 ϩ T-cell activation compared with injection of wild-type H-Y cells. 36 In this model, H-Y-specific antigen presentation was reduced after transfer of ␤ 2 -microglobulin donor cells compared with wild-type cells 11 days after transfer, and the authors suggested that long-lived antigen is required for DC licensing and helper-dependent CD8 ϩ T-cell activation. However, using K b -deficient target cells, we find a rapid clearance and a robust helper-dependent CD8 ϩ T-cell response 8 days after injection of target cells, implying that antigen persistence is not a determinant in our model.…”

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

“…It is likely that our results underestimate the differences described as the T cells were stimulated and transferred separately. If anything, CD4 + T cells assist APCs in Ag presentation to CD8 + T cells, whereas CD8 + T cells rather limit APC availability for their CD4 + counterparts (30,32,33).…”

“…Two studies supplied evidence for the notion that TCRtriggered CD4 + T cells keep proliferating in the absence of Ag and cytokines (22,23), whereas others did not support such an early-programming scenario but rather supplied evidence for the importance of maintained TCR signals (24)(25)(26)(27). Most of the experiments done in vivo supported the Ag dependency of CD4 + T cells throughout the expansion phase (8,13,(28)(29)(30)(31)(32)(33).…”