Apoptotic cells induce dendritic cell-mediated suppression via interferon-γ-induced IDO

Centre for Research in Biomedicine, Faculty of Applied Sciences, University of the West of England, Bristol BS16 1QY, United Kingdom.
Immunology (Impact Factor: 3.8). 06/2008; 124(1):89-101. DOI: 10.1111/j.1365-2567.2007.02743.x
Source: PubMed


Dendritic cells (DC) are sensitive to their local environment and are affected by proximal cell death. This study investigated the modulatory effect of cell death on DC function. Monocyte-derived DC exposed to apoptotic Jurkat or primary T cells failed to induce phenotypic maturation of the DC and were unable to support CD4+ allogeneic T-cell proliferation compared with DC exposed to lipopolysaccharide (LPS) or necrotic cells. Apoptotic cells coincubated with LPS- or necrotic cell-induced mature DC significantly suppressed CD80, CD86 and CD83 and attenuated LPS-induced CD4+ T-cell proliferation. Reduced levels of interleukin-12 (IL-12), IL-10, IL-6, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) were found to be concomitant with the suppressive activity of apoptotic cells upon DC. Furthermore, intracellular staining confirmed IFN-gamma expression by DC in association with apoptotic environments. The specific generation of IFN-gamma by DC within apoptotic environments is suggestive of an anti-inflammatory role by the induction of indoleamine 2,3-dioxygenase (IDO). Both neutralization of IFN-gamma and IDO blockade demonstrated a role for IFN-gamma and IDO in the suppression of CD4+ T cells. Moreover, we demonstrate that IDO expression within the DC was found to be IFN-gamma-dependent. Blocking transforming growth factor-beta (TGF-beta) also produced a partial release in T-cell proliferation. Our study strongly suggests that apoptosis-induced DC suppression is not an immunological null event and two prime mediators underpinning these functional effects are IFN-gamma-induced IDO and TGF-beta.

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    • "Several reports have shown that interaction and/or internalization of apoptotic cells by immature DCs does not induce expression of the DC maturation-markers MHC class II, CD40, CD80, CD86, and CD83 in vitro or in vivo, even after challenge with LPS, CD40 signaling, TNF-α, or monocyte-conditioned medium [143–146]. Additionally, DCs that internalize cells in early apoptosis exhibit a selective decrease in the levels of mRNA and secretion of the proinflammatory cytokines IL-1α, IL-1β, IL-6, IL-12p70, and TNF-α, while secreting normal or increased amounts of immunosuppressive transforming growth factor (TGF)-β1 and IL-10, even in the presence of LPS [147–149]. DCs that acquire antigens from apoptotic cells efficiently present apoptotic cell-derived peptides to CD4 T cells and cross-present the internalized antigen to MHC class I-restricted CD8 cytotoxic T cells [150–153]. However, DCs exposed to apoptotic cells show a decrease in their ability to stimulate T cells, a phenomenon that seems to be related to the inhibitory effect of apoptotic cells on the amount of expression of MHC and costimulatory molecules, rather than to a defect in the antigen processing function of the APC [132, 144, 145, 154]. "
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    • "It has been demonstrated that a distinct group of DCs with suppressive function emerge after exposure to certain cytokines or when the DCs re-differentiation in different stromal microenvironments [3], [4], [5]. The cytokines or factors produced by DCs, such as transforming growth factor-beta (TGF-beta), IL-10, indoleamine 2,3-dioxygenase (IDO), and NO, may play an important role in the regulation of immune responses [1], [6], [7], [8], [9]. In our previous studies, we demonstrated that NO production is a significant characteristic of regulatory DCs derived from mature DCs co-cultured with splenic or hepatic stroma [3], [10] and that this NO exerts direct, rapid and potent inhibitory effects on T cell proliferation. "
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