Long-Term Exposure to Inflammation Induces Differential Cytokine Patterns and Apoptosis in Dendritic Cells

Abstract

The activation of dendritic cells (DCs) has profound implications and governs the control of adaptive immunity. However, long-term activation might drive exhaustion of immune cells and negatively affect functionality. Here, long-term vs. short-term exposure to bacterial lipopolysaccharide and interferon (IFN)γ was evaluated on human monocyte-derived DCs. Long-term activated DC1s began to undergo apoptosis concomitant with a profound TAM-receptor and efferocytosis-dependent induction of interleukin (IL)-10. Whereas, levels of IL-12p70 and IL-10 were positively correlated upon short-term activation, an inverse association occured upon long-term activation and, while short-term activated CD1a+ DCs were main producers of IL-12p70, CD1a− DCs were the main fraction that underwent apoptosis and released IL-10 upon long-term activation. Moreover, pre-apoptotic long-term activated DCs were no longer able to activate alloreactive IFNγ-responsive T cells present in peripheral blood mononuclear cells from healthy volunteers. The IFNγ response was mediated by IL-12p70, as a strong reduction in IFNγ was observed following blockade with an IL-12p70 neutralizing antibody. Finally, multiplex analysis of DC supernatants revealed a particular pattern of proteins associated with apoptosis, cancer and chronic inflammation partly overlapping with gold standard DCs well-known for their inability to secrete IL-12p70. In conclusion, long-term activated DC1s significantly changed their profile toward a non-functional, tumor-promoting and anti-inflammatory phenotype.