Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia.
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Cell Rep. 2024 Feb 27;43(2):113754. doi: 10.1016/j.celrep.2024.113754. Epub 2024 Feb 13.
Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3-4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor β partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.
血源性病原体可引起全身炎症反应综合征（SIRS），随后出现持续时间长、潜在致命的免疫抑制。导致 SIRS 后免疫受损的机制尚不清楚。我们发现，由病原体模拟物或疟疾感染引发的 SIRS 可导致常规树突状细胞（cDC）功能瘫痪。瘫痪影响了几代 cDC，并使免疫功能受损 3-4 周。瘫痪的 cDC 显示出独特的转录组和表型特征，并表现出在体内捕获和呈递抗原的能力受损。它们在受到刺激时也显示出改变的细胞因子产生模式。瘫痪程序不是在骨髓中启动的，而是在外周组织中在 SIRS 消退后持续存在的局部二级信号的影响下，在 cDC 最终分化过程中启动的。用针对 cDC 受体的单克隆抗体进行疫苗接种或阻断转化生长因子-β部分克服了瘫痪和免疫抑制。这项工作提供了对瘫痪机制的深入了解，并描述了恢复 SIRS 后免疫能力的策略。
