Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15-and IL1-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes

Background: Immunological memory is maintained by antigen-independent tonic stimulation. Results: Stress-treated dendritic cells stimulate IL-15- and IL-1-mediated pathways, required for optimum memory T cell induction. Conclusion: Stress agents may be responsible for the persistence of immunological memory, involving an epigenetic mechanism. Significance: Repetitive stress may account for tonic stimulation, which maintains immunological memory. The prevailing evidence suggests that immunological memory does not require antigenic re-stimulation but is maintained by low level tonic stimulation. We examined the hypothesis that stress agents contribute to tonic cellular activation and maintain immunological memory. Stimulation of monocyte-derived dendritic cells (DC) with stress agents elicits reactive oxygen species and HSP70. NFB is activated, which up-regulates membrane-associated (ma) IL-15, caspase-1 and IL-1. Co-culture of stress-treated DC with mononuclear cells activates IL-15 and IL-1 receptors on CD4(+) T cells, eliciting CD40L, proliferation, and up-regulation of CD45RO(+) memory T cells. The transcription factors Tbet(high) and RORt are up-regulated, whereas FoxP3 is down-regulated, resulting in enhanced Th1 and Th17 expression and the corresponding cytokines. The interaction between maIL-15 expressed by DC and IL-15R on CD4(+) T cells results in one pathway and the corresponding cells expressing IL-1 and IL1R as a second pathway. Importantly, inhibition studies with IL-15 antibodies and IL-1R inhibitor suggest that both pathways may be required for optimum CD4(+) CD45RO(+) memory T cell expression. Type 1 IFN expression in splenic CD11c DC of stress-treated mice demonstrated a significant increase of IFN- in CD11c CD317(+) and CD8(+) DC. Analysis of RNA in human CD4(+) memory T cells showed up-regulation of type 1 IFN-stimulated genes and inhibition with histone methyltransferase inhibitor. We suggest the paradigm that stress-induced tonic stimulation might be responsible for the robust persistence of the immune response in vaccination and that epigenetic changes are involved in maintaining CD4(+) T cell memory.