■先天免疫训练是一种新陈代谢,功能,以及由不同刺激触发的先天细胞的表观遗传长期重编程。这种印记也到达骨髓中的造血前体以维持记忆样表型。树突状细胞(DC)可以表现出类似记忆的反应,在随后暴露于病原体时增强;然而,这种印记是否是血统和刺激限制仍在确定中。然而,DCs训练对非感染性疾病的适应性和保护性免疫应答的功能影响仍未解决。
■我们评估了无毒霍乱B亚基(CTB)的作用,通过TNFa和LDH表达揭示的LPS和LTA在鼠DC中诱导训练的免疫力,通过共聚焦显微镜。此外,我们从用CTB处理的小鼠中获得骨髓DC(BMDC),LPS,和LTA,并使用多参数细胞计数评估DC的训练特征及其抗原呈递细胞能力。最后,我们设计了一个实验性黑色素瘤小鼠模型,以证明CTB训练的DC在体内诱导的保护作用。
■CTB训练的DC表现出TNFa的表达增加,和LDH表达指示的代谢重编程。此外,CTB培训在DC前体上有印记,增加BMDCs的数量和抗原呈递功能。我们发现通过CTB训练刺激皮肤和淋巴结处DC前体的募集和DC浸润。有趣的是,CTB诱导的训练可促进肿瘤浸润性DC(CD86)中的高度共刺激表型和耗尽的CD8T细胞(Ki67,GZMB+),这与体内针对黑色素瘤攻击的保护性反应有关。
■我们的工作表明,CTB可以诱导DCs的先天免疫训练,在黑色素瘤模型中转化为有效的适应性免疫反应,可能是控制肿瘤生长的潜在免疫治疗方法。
UNASSIGNED: Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved.
UNASSIGNED: We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo.
UNASSIGNED: CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo.
UNASSIGNED: Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.