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tel-00827710, version 1 - 29 May 2013 compared to the antigen administered alone. Although the adjuvant theorically could still promote the immune response further, the lack of this effect is most likely due to being past the time point when type I IFN has already acted to promote antigen survival and processing. Interesting results have also been obtained regarding the effects of poly I:C and type I IFN effects at the level of CD8 + T cells. Several groups have demonstrated a direct effect of type I IFN on T cells (Le Bon et al., 2006; Kolumam et al., 2005). Additionally, Marshall and colleagues studied the effects of type I IFN released after viral infection on bystander T cells that are not specific for the viral antigens. They demonstrated that type I IFN sensitize bystander T cells, leading to enhanced effector functions, such as IFNγ secretion, upon stimulation with their cognate antigen. Similar effects were observed after poly I:C administration and prior to immunization with antigen. It was shown that these effects were also due to IFN, acting indirectly on bystander T cells (Marshall et al., 2010). In a follow-up study, the same group observed that IFN released upon viral infection or poly I:C treatment resulted in a transient immunosuppression and inhibition of T cell proliferation depending on the timing of its stimulation and production. Likewise, IFN was able to act as a stimulatory adjuvant when bystander T cells were exposed to the inflammatory milieu and cognate antigen at the beginning of type I IFN production, whereas an immunosuppressive effect on T cell proliferation was observed when T cells encountered the antigen after prior exposure to type I IFN (Marshall et al., 2011). These mechanisms may also play a role in our model and contribute to the pleiotropic roles of poly I:C and downstream type I IFN production on cross- priming. 156
tel-00827710, version 1 - 29 May 2013 Figure 52. Differential effects of adjuvant depending on the timing of delivery. (A) Cross-priming occurs after immunization with a cell-associated antigen in the absence of adjuvant. (B,C) Poly I:C was administered either early (B) or late (C) after immunization. These time points correspond to conditions where antigen was already engulfed by DCs (C) or prior to antigen uptake (B). Some effects of poly I:C are highlighted by red numbers: (1) DC recruitment in lymph node, (2) DC maturation and (3) T cell retention in lymph node. DLN, draining lymph node. The grey T cells correspond to activated T cells. Page 157 of 256
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tel-00827710, version 1 - 29 May 2013<br />
Figure 52. Differential effects of adjuvant <strong>de</strong>pending on the timing of <strong>de</strong>livery. (A) Cross-priming<br />
occurs after immunization with a cell-associated antigen in the absence of adjuvant. (B,C) Poly I:C<br />
was administered either early (B) or late (C) after immunization. These time points correspond to<br />
conditions where antigen was already engulfed by DCs (C) or prior to antigen uptake (B). Some<br />
effects of poly I:C are highlighted by red numbers: (1) DC recruitment in lymph no<strong>de</strong>, (2) DC<br />
maturation and (3) T cell r<strong>et</strong>ention in lymph no<strong>de</strong>. DLN, draining lymph no<strong>de</strong>. The grey T cells<br />
correspond to activated T cells.<br />
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