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

Abstract

Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-β/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

“…AP‐3 controls a different TLR trafficking step in conventional DCs (cDCs), facilitating the recruitment of TLR4 and likely other TLRs to maturing phagosomes following uptake of bacteria and other large particles. Reduced TLR recruitment to phagosomes in AP‐3‐deficient mice and HPS2 patients results in impaired proinflammatory signaling by bacterial stimuli and reduced antigen presentation of phagocytosed antigens to CD4+ T cells, with consequent skewing of CD4+ T cell responses toward the Th2 lineage and altered cDC maturation and chemokine responses . Additionally, AP‐3 plays a role in dampening autophagic responses to pathogenic bacteria in cDCs.…”

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

“…The AP3 adaptor complex is critical for cargo-selective transport of CpG DNA/TLR/MyD88 complexes to specialized endosomes where they can recruit IRF7 for IFN-I production (Blasius et al, 2010;Sasai et al, 2010;Prandini et al, 2016). To our knowledge, the role of AP3 in pDC response to stimulation with viruses was assessed exclusively in vitro (Blasius et al, 2010;Prandini et al, 2016). Therefore, we compared the cell-intrinsic impact of AP3 loss on in vivo pDC responses to MCMV infection versus CpG injection ( Fig 3E and F).…”

Hermansky–Pudlak syndrome: Mutation update

“…The AP‐3 immunodeficiency also involves defective AP‐3‐mediated lytic granule exocytosis in NK‐cells and cytotoxic T cells (Clark et al, 2003; Fontana et al, 2006; Gil‐Krzewska et al, 2017; Jung et al, 2006). AP‐3 deficient dendritic cells showed impaired toll‐like receptor recruitment (Mantegazza et al, 2012; Sasai, Linehan, & Iwasaki, 2010), leading to defects in interferon production and antigen presentation in these cells from HPS‐2 subjects (Prandini et al, 2016). AP‐3‐dependent inflammasome positioning and activation was shown in dendritic cells from HPS‐2 mice (Mantegazza et al, 2017).…”

“…AP-3 deficient dendritic cells showed impaired toll-like receptor recruitment (Mantegazza et al, 2012;Sasai, Linehan, & Iwasaki, 2010), leading to defects in interferon production and antigen presentation in these cells from HPS-2 subjects (Prandini et al, 2016). AP-3-dependent inflammasome positioning and activation was shown in dendritic cells from HPS-2 mice (Mantegazza et al, 2017).…”