Biology subjects

Mennechet, F. J.

Publications and source records attributed to Mennechet, F. J..

2 recordsLinked to original sources

bioRxiv2022

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

Innate lymphoid cells (ILCs), the complements of diverse CD4 T helper cells, help maintain tissue homeostasis by providing a link between innate and adaptive immune responses. While pioneering studies over the last decade have advanced our understanding how ILCs influence adaptive immune responses to pathogens, far less is known about whether the adaptive immune response feeds back into an ILC response. In this study, we isolated ILCs from blood of healthy donors, fine-tuned culture conditions, and then directly challenged them with human adenoviruses (HAdVs), with HAdVs and host defence proteins (HDPs) or neutralizing antibodies (NAbs), to mimic interactions in a host with pre-existing immunity. Additionally, we developed an ex vivo approach to identify how bystander ILCs respond to the uptake of HAdVs {+/-} neutralizing antibodies by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces phenotypic maturation and cytokine secretion. Moreover, NAbs and HDPs complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact adenovirus-based vaccine efficacy. Author SummarySeveral studies have shown the importance of innate lymphoid cells (ILCs) both from an immune and physiological point of view, in particular for their role in the maintenance of tissue integrity, pathogens clearance, or in the establishment of immune tolerance. Our study focuses on the role of ILCs during direct challenge with prototype vaccines based on human adenoviruses (HAdVs) {+/-} host defence proteins (HDPs) or neutralizing antibodies (NAbs) to mimic interactions in a host with pre-existing immunity. In parallel, through an ex vivo approach we observe how bystander ILCs respond to the uptake of HAdVs {+/-} NAbs by monocyte-derived dendritic cells. We show that ILCs take up HAdVs, which induces pro- inflammatory and antiviral responses through phenotypic maturation and cytokine secretion. Moreover, HAdV-NAb and HAdV-HDP complexes modified the cytokine profile generated by ILCs, consistent with a feedback loop for host antiviral responses and potential to impact HAdV vaccine efficacy.

immunology↗

bioRxiv2018

Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregs are generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naive T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.\n\nAuthor summaryWhile numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus-antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.

microbiology↗