Abstract A079: Secreted IL-12p70 from long-term activated dendritic cells is lost concomitant with their apoptosis and release of IL-10

Abstract

The intimate balance between peripheral tolerance and adaptive immunity has profound implications in several disease settings. Interleukin-12 (IL-12) plays a major role in immunity to intracellular pathogens and cancer by controlling IFNγ-dependent adaptive immunity. The transient production of the bioactive IL-12p70 heterodimer and the concurrent expression of interleukin-10 (IL-10) serves as a myeloid checkpoint to avoid immunopathology. Here, long-term exposure to inflammatory stimuli was evaluated on monocyte-derived dendritic cells (DCs) activated with lipopolysaccharide (LPS) and gamma interferon (IFNγ). The secretion of IFNγ from co-cultures with allogeneic T-cells present in peripheral blood mononuclear cells from healthy volunteers served as a measure of T-cell activation.The secretion of IFNγ from co-cultures was progressively lost as exposure of DCs to inflammatory stimuli was extended from one up to four days prior to co-culture or following IL-12p70 antibody-mediated blockade. Most pronounced was the 12-fold reduction (N = 9 donor pairs) seen with four-day activated DCs. Furthermore, at four days of activation, a significant fraction of DCs underwent apoptosis concomitant with their increased release of IL-10 and a striking 10-fold drop in levels of IL-12p70 as compared with DCs activated one, two or three days. Furthermore, after four days of activation, DC-derived IL-12p70 was inversely correlated with IL-10 and with IFNγ derived from co-cultures. It is currently an open question whether IL-12p70 naturally degrades after four days of activation or whether apoptotic DCs actively stimulate the degradation of IL-12p70. Citation Format: Morten Hansen, Laura Stentoft Carstensen, Andreas Obers, Inge Marie Stentoft Svane. Secreted IL-12p70 from long-term activated dendritic cells is lost concomitant with their apoptosis and release of IL-10 [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A079.