IgG-Complexed Adenoviruses Induce Human Plasmacytoid Dendritic Cell Activation and Apoptosis

Abstract

Following repeat exposure to many human adenoviruses (HAdVs), most adults harbour long-lived B- and T-cell responses. Combined, this response typically protects us for years from re-infection by the same HAdV type. In spite of these immune responses, some HAdV types are associated with persistent infections that constitute a life-threatening risk when an individual’s T-cell response is compromised. By contrast, patients with B-cell deficiencies do not appear to be at a greater risk of HAdV disease. This dichotomy begs the question of the secondary role of anti-HAdV antibodies during host defence. In this study, we explored IgG-complexed (IC)-HAdV5 and primary human plasmacytoid dendritic cell (pDC) interactions. We found that IC-HAdV5 are efficiently internalized in pDCs, stimulate their activation through TLR9 signalling, and cause apoptosis. These data may help reconcile the enigma of robust immune response to HAdVs, while concurrently allowing persistence.

Human innate lymphoid cell activation by adenoviruses is modified by host defence proteins and neutralizing antibodies

“…Yet, these same sera can increase HAdV uptake by professional APCs via FcγRIII (CD16) [34, 50]. FcγR-mediated uptake also increases the phenotypic and functional maturation of moDCs and plasmacytoid DCs [25,33,34,50]. By contrast, Ab that neutralize HAdV-B35 infection of epithelial cells also decreased transgene expression in DCs [51].…”

“…The cytoplasmic content of neutrophils can be as much as 20% HDPs, effector molecules of the innate immune system. Moreover, we previously showed that human neutrophil protein-1 (HNP-1) and lactoferrin bind to HAdV-C5, -D26 and -B35 and, by acting as bridges via TLR4, increase HAdV uptake by DCs [25][26][27][28].…”

“…Then, we quantified ILC uptake of HAdV-C5, -D26, and -B35 alone, or in complex with host defence proteins (HDPs), or neutralizing antibodies (NAbs) [25][26][27][28]. We characterized the levels of potential HAdV receptors, receptors for HDP-and NAb-complexed HAdVs, and relevant pattern recognition receptors (PRRs).…”

Adenovirus receptors on antigen‐presenting cells of the skin

“…The interaction of the RGD motifs of the penton base with integrins can increase internalization efficacy in some cell types (Nemerow & Stewart, 1999;Storm et al, 2017;Wickham et al, 1993). Of note, monocytes, and monocyte-derived, myeloid, and plasmacytoid DCs (moDC, mDC, pDC, repectively) are CAR-negative (Chéneau et al, 2021;Eichholz et al, 2016;Soudais et al, 2000;Tran et al, 2018Tran et al, , 2021. Exceptions to this trend of CAR-negative immune cells are LCs and dermal DCs (Adams et al, 2009).…”

Editorial: Adenoviral Infection and Immunity, and Adenoviral Vectors for Gene Therapy Applications

“…Although HAdVs have been found for almost 70 years and many of their basic properties have been discovered, some important molecular mechanisms such as the infection and innate immunity in epithelial cells, immune cells, and hematopoietic stem cells still need to be entirely characterized. To date, interactions between HAdVs and host factors and the antiviral immunity in vivo have been investigated preliminarily ( Chéneau et al ; Tran et al, 2021 ; Eichholz et al, 2022 ), which still needs further investigation. HAdV vector-based gene therapy shows broad application potentials.…”