Type I IFN regulate DC turnover in vivo

Abstract

DC are the most potent antigen-presenting cells that recognise signs of infection and serve as the main activators of naïve T cells. We have previously shown that type I IFN (IFN-I) are produced by DC and can act in an autocrine manner to activate DC. In the present study, we have investigated the role of IFN-I in regulating the turnover and lifespan of DC. We found that DC, especially the CD8a 1 subset, from type I IFN receptor knock out (IFNAR KO) mice, display a reduced turnover rate when compared with DC from WT mice, as revealed by BrdU labelling kinetics. In vitro, IFNAR KO BM precursor cells cultured in the presence of GM-CSF generated CD11c 1 DC less efficiently than WT BM, and the IFNAR KO DC that arose displayed reduced migratory ability. Interestingly, splenic DC from IFNAR KO mice exhibited a higher survival rate in short-term culture compared with control DC. Exposure to IFN-I in vivo markedly increased the turnover rate of splenic DC, particularly CD8a 1 DC, which was preceded by a transient induction of apoptosis. In accordance with this, IFN-I stimulated the apoptosis of splenic DC in vitro. Overall, our data indicate that IFN-I are important regulators of DC turnover in vivo and suggest that these cytokines may exert this function through the modulation of multiple processes involving DC apoptosis, proliferation and migration.

Type I IFNs Control Antigen Retention and Survival of CD8α+ Dendritic Cells after Uptake of Tumor Apoptotic Cells Leading to Cross-Priming

“…This finding, as opposed to our previous finding showing IFN-I exerting proapoptotic effects on bystander (i.e., in the absence of Ag) DC, suggests an elegant regulatory mechanism by which IFN-I selectively sustain the life span of Ag-bearing DC for induction of effective immune responses, while favoring a rapid clearance of steady-state DC (15). The duration of DC life span critically regulates the efficiency of cross-priming and the outcome of adaptive immunity, although little is known about the role of Ag persistence in this process (29).…”

“…4E). These results confirm our previous findings on the proapoptotic effects of IFN-I on bystander DC (15) and suggest that these cytokines may instead act as a survival factor for Ag-bearing DC. Fig.…”

“…The procedure of splenic DC isolation has been described in detail elsewhere (15). Briefly, total splenocytes were subjected to density-gradient centrifugation in Nycodenz solution (1077 g/ml; Life Technologies).…”

Cyclophosphamide Synergizes with Type I Interferons through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis

“…Recent reports showed that IFN-I reactivate dormant hematopoietic stem cells, promoting their proliferation and mobilization in vivo (39,40). In addition, IFN-I can directly stimulate the turnover of DC in vivo, especially of CD8a þ DC, and promote the generation of DC from BM precursors (21,24). Our findings support the role of IFN-I in homeostasis, with crucial implications for patients undergoing myelodepleting regimens, as concomitant treatment with IFN-a could accelerate recovery of immune competence (25).…”

“…One critical feature of DC for inducing efficient antitumor response is the capacity to cross-present tumorassociated antigens (Ag) and to cross-prime cytotoxic T cells, a process requiring appropriate activation stimuli (19,20). Among signals capable of "licensing" DC, IFN-I have been described to stimulate DC activation, homeostasis, migration, T-cell priming, and cross-priming (21)(22)(23)(24)(25). Indeed, IFN-I are cytokines with a long record of clinical use for the treatment of several types of malignancies due to their capacity to exert antitumor activity through multiple mechanisms (26).…”