Microbiology & Immunology - Theses
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ItemMechanisms that cause functional impairment of dendritic cells following Systemic Inflammatory Response Syndrome( 2022)Dendritic cells (DC) are potent antigen presenting cells which link the adaptive and innate arms of immune response. This normal functioning of DC is severely impaired following recovery from systemic (pro- and anti-)inflammatory response syndrome (SIRS) caused by sepsis or severe trauma, leading to protracted immunosuppression. This so-called “DC paralysis” results in greater risk of secondary infections and higher rates of mortality and morbidity in patients. We modelled SIRS, DC paralysis and immunosuppression in mice after injecting Toll-like receptor (TLR) ligands or malaria infection. Transcriptome and phenotype characterization allowed us to recognize and track paralyzed DC. Functional characterization of paralyzed DC showed normal activity in terms of antigen uptake, T cells priming and cytokine production in vitro. But, paralyzed DC in vivo or ex vivo showed impairments in uptake of antigen, defects in antigen processing and presentation by MHC molecules, altered cytokine production, and elevated production of inhibitory molecules, altogether leading to impaired priming of antigen-specific T cells by paralyzed DC. We were able to improve paralyzed DC function by targeting antigen to a surface receptor or by blocking interferon type I signaling. However, blocking IL-10 signaling, ablation of prominent paralysis marker CD103 or transcription factor Pparg, and depletion of regulatory T cells did not improve function of paralyzed DC. We further showed formation of paralyzed DC did not need DC activation or recognition of TLR ligand, but was instructed by secondary signals after SIRS including TGFb, produced by paralyzed DC themselves. We observed increased number of immediate DC precursors in spleen after SIRS, and performed transfer experiments to understand the developmental stage that paralysis was imprinted on cells of DC lineage. We observed no commitment at any stages of DC development towards paralyzed fate, and that local tissue environment biased the final stages of DC development towards paralysis in situ. We also showed location-specificity of DC paralysis as systemic SIRS caused paralysis in spleen and peripheral lymph nodes but not in lung, and SIRS in lung caused immunosuppression in lung but not in spleen. We finally showed severe trauma (as aseptic cause of SIRS) could lead to DC activation and paralysis. We ultimately aim to translate the understanding from mouse into the clinic towards diagnosis and treatment of DC paralysis in critically-ill patients.