A Default Pathway of Memory CD8 T Cell Differentiation after Dendritic Cell Immunization Is Deflected by Encounter with Inflammatory Cytokines during Antigen-Driven Proliferation

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Abstract
Inflammatory cytokines induced by infection or vaccination with adjuvant act directly or indirectly on CD8 T cells to modulate their expansion, contraction, and acquisition of memory characteristics. Importantly, the initial exposure of naive T cells to inflammatory cytokines may occur before, during, or after their interaction with stimulating dendritic cells (DC) and it is unknown whether and how the timing of cytokine exposure impacts the CD8 T cell response. In this study, we use an immunization strategy with peptide-coated mature DC that, in the absence of inflammatory cytokines, results in a transient effector phase followed by the accelerated acquisition of memory characteristics by the responding CD8 T cells. Induction of inflammatory cytokines by TLR agonists, at the time of DC immunization or 2–4 days after DC immunization, prevented the early acquisition of memory characteristics by the responding CD8 T cells. Interestingly, although induction of inflammatory cytokines at the time of DC immunization increased the effector response, induction of inflammatory cytokines after DC immunization did not promote further expansion of the responding CD8 T cells but still prevented their early acquisition of memory characteristics. In contrast, induction of inflammatory cytokines 2 days before DC immunization did not prevent the CD8 T cells from early acquisition of memory characteristics. Furthermore, TLR ligand-induced inflammatory cytokines had the most significant impact on the phenotype and function of proliferating CD8 T cells. These data suggest that a default pathway of memory CD8 T cell differentiation is deflected toward sustained effector commitment by encounter with inflammatory cytokines during Ag-driven proliferation.