Interferon-α Production by Plasmacytoid Dendritic Cells Is Dispensable for an Effective Anti-Cytomegalovirus Response in Adaptor Protein-3-Deficient Mice

Abstract

Adaptor protein-3 (AP-3) is a heterotetrameric complex, which regulates vesicular trafficking. Mutations of the b3A subunit cause the Hermansky-Pudlak syndrome type 2 (HPS-2), a rare genetic disease characterized by albinism, platelet defects, and recurrent infections. Likewise, pearl mice, which lack functional AP-3, show several HPS-2 defects. The AP-3 absence results in defective toll-like receptor trafficking and signaling in dendritic cells (DC), but its effect on the efficiency of the in vivo antiviral response is unclear. We evaluated the impact of AP-3 deficiency on the distribution of DC subsets, interferon (IFN) production, and the susceptibility to murine cytomegalovirus (MCMV) infection. Pearl mice showed a distribution and frequency of conventional (cDC) and plasmacytoid DC (pDC) similar to that of wild-type mice both before and after MCMV infection. Moreover, pearl mice controlled MCMV infection even at high virus doses and showed a normal production of IFN-a. Since pDC, but not cDC, from pearl mice showed an impaired IFN-a and tumor necrosis factor-a production in response to prototypic DNA (MCMV and Herpes Simplex virus) or RNA (Vesicular Stomatitis virus) viruses in vitro, it is likely that MCMV infection can be controlled in vivo independently of an efficient production of IFN-a by pDC, and that the AP-3 complex has a minimal impact on protective antiviral responses.

Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection

“…Based on this observation, the authors inferred that pDC were unable to produce high levels of IFN-I in MCMV-infected Ap3b1 À/À mice but that this did not lead to a decrease in the peak serum levels of these cytokines. Thus, without measuring cytokine production in pDC in vivo, they concluded that pDC are dispensable for high systemic IFN-I production during MCMV infection (Del Prete et al, 2015), which is in contradiction with previous reports (Dalod et al, 2002(Dalod et al, , 2003Krug et al, 2004;Swiecki et al, 2010;Cocita et al, 2015). Here, we showed that Ap3b1 À/À pDC mount normal cytokine responses in vivo during MCMV infection.…”

“…The lack of AP3 requirement for pDC IFN-I production during MCMV infection is consistent with the normal levels of circulating IFN-I in the sera of MCMV-infected Ap3b1 À/À mice (Del Prete et al, 2015). However, our conclusions drastically differ from those of that previous report.…”

Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

“…pDCs have previously been demonstrated to be required for the control of several viral infections, including herpes simplex virus (HSV), murine hepatitis virus (MHV), murine cytomegalovirus (MCMV), vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV) ( Swiecki and Colonna, 2015 ). In contrast, others reported that pDCs are dispensable and/or do not contribute to IFN-I production in the case of certain infections, including influenza virus, respiratory syncytial virus (RSV), Newcastle disease virus (NDV) and MCMV ( Del Prete et al, 2015 ; GeurtsvanKessel et al, 2008 ; Jewell et al, 2007 ; Kumagai et al, 2007 ; Swiecki et al, 2013 ), which may be a reflection of viral replication mechanisms, inoculum size, or location ( Swiecki et al, 2010 ; Swiecki et al, 2013 ). These observations bring the emerging concept that while antiviral response (i.e.…”

Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency

“…Interestingly, analysis of blood cell counts in pearl mice has shown that the number of conventional DC and pDC is normal. 16 Likewise, pearl mice are not neutropenic and do not have cyclic neutropenia, two events observed in HPS2 patients and canine cyclic hematopoiesis in dogs, respectively. 17 Altogether, these observations highlight differences between HSP2 patients and the pearl mouse model.…”

“…This is in accord with previous observations 11,12 and with the finding that pDCs from pearl mice fail to secrete type I IFN after murine cytomegalovirus infection in vitro. 16 …”