Immune crosstalk through shared LN drainage in the digestive system

项目摘要/摘要 假设：胰腺疾病危及生命，包括胰腺癌(PDAC)，影响 外分泌细胞和自身免疫性糖尿病(T1D)，破坏产生胰岛素的β细胞。外部因素，如 感染和饮食被认为是触发因素，但疾病的起源仍然难以捉摸，也缺乏治疗方法。这个 免疫系统极大地促进了疾病的进展，但控制胰腺获得性免疫的是什么 对Tone的研究不足，阻碍了有效的免疫靶向治疗。淋巴结(LN)是卵巢癌的关键部位。 启动组织特异性适应性免疫，这里我们假设胰腺之间共享层粘连蛋白 十二指肠和肝脏影响胰腺免疫的性质。我们假设，这两位少校 这些共同排出的器官的淋巴输出以及它们更直接地暴露在环境扰动中，使得 它们决定了LN环境，从而在动态平衡期间影响胰腺适应性免疫细胞的命运 以及肠道或肝脏的侮辱。最后，我们提出了迁移性树突状细胞(DC)呈现 胰腺抗原是这种免疫串扰的关键细胞靶点。 这一假设将在我们的特定目标(SA)中得到验证：SA#1将表征 胰腺抗原负载树突状细胞对胰腺外分泌或内分泌特异性T细胞的影响 动态平衡期间共引流的淋巴结节的极化。SA#2将测试LN DC和T细胞的程度 随着肠道和肝脏的扰动，例如感染，命运会发生变化。SA#3将评估亲属 与肝脏和肠道共享LNS对外分泌和内分泌中T细胞景观的重要性 作为原则的证明，将研究十二指肠感染如何通过LN共享， 影响胰腺组织T细胞和T1D的进展。 独特的方法：1.我们将通过追踪组织特异性抗原来鉴定装载有胰腺抗原的LN DC 抗原生物素化或荧光蛋白摄取。2.我们已经培育出新的小鼠，可以表达 来自外分泌或内分泌胰腺、肝脏或肠道的模型抗原OVA，允许监测OVA特异性 T细胞的命运。这种方法允许系统地比较LNS中组织特异性T细胞反应 与肝脏和十二指肠共用。 影响：该项目将提供有关胰腺免疫如何形成的基本见解 环境波动。而通过LN共享的胰腺扰动的潜在来源，肝脏和 十二指肠可能成为胰腺治疗干预的解剖学途径。从机械上讲， 研究将增加我们对组织中DC印记与LN的理解，以及这种“可塑性”的影响 关于口述T细胞的反应。更广泛地说，该提案的特点是器官之间共享LN 无法识别的塑造组织特异性免疫的力量。

PROJECT SUMMARY/ABSTRACT Hypothesis: Diseases of the pancreas are life-threatening, including pancreatic cancer (PDAC), affecting exocrine cells, and autoimmune diabetes (T1D), destroying insulin-producing β cells. External factors like infections and diet are implicated as triggers, but the disease origins remain elusive and cures are lacking. The immune system strongly contributes to disease progression, but what governs pancreatic adaptive immune tone is understudied, preventing effective immune-targeting therapy. Lymph nodes (LNs) are key sites for the initiation of tissue specific adaptive immunity, and here we hypothesize that LN sharing between pancreas and duodenum and liver influences the nature of pancreatic immunity. We postulate that both, the major lymph output from these co-drained organs and their more direct exposure to environmental perturbation, allow them to dictate LN environments, thus impacting pancreatic adaptive immune cell fate both during homeostasis and upon intestinal or hepatic insults. Finally, we propose that migratory dendritic cells (DCs) presenting pancreatic antigen are the key cellular target for such immune cross talk. This hypothesis will be tested in our Specific Aims (SA): SA #1 will characterize the phenotype of pancreatic antigen loaded DC and consequences for exocrine or endocrine pancreas specific T cell polarization in the co-drained LNs during homeostasis. SA #2 will test to what extent LN DCs and T cell fates change upon intestinal versus hepatic perturbation such as infections. SA #3 will assess the relative importance of sharing LNs with liver versus gut for the T cell landscape back in the exocrine and endocrine pancreatic tissue and, as a proof of principle, will investigate how duodenal infection, through LN sharing, affects pancreatic tissue T cells and the progression of T1D. Unique approach: 1. We will identify LN DCs loaded with pancreatic antigen by virtue of tracking tissue specific antigen biotinylation or fluorescent protein uptake. 2. We have generated novel mice that permit expression of the model antigen OVA from exocrine or endocrine pancreas, liver or gut, allowing for monitoring OVA specific T cell fate. This method permits the systematic comparison of tissue-specific T cell responses in the LNs shared with the liver versus the duodenum. Impact: This project will provide fundamental insights into how pancreatic immunity may be shaped by environmental fluctuations. While potential sources of pancreatic perturbation through LN sharing, liver and duodenum could turn out as anatomical routes for therapeutic intervention in the pancreas. Mechanistically the research will increase our understanding of DC imprinting in tissue versus LN and the impact of this “plasticity” on dictating T cell responses. More broadly, the proposal features LN sharing between organs as a previously unrecognized force shaping tissue specific immunity.