Mechanism of cDC2 subset differentiation in peripheral organs

项目摘要 传统的树突状细胞(CDCs)对于天然免疫和获得性免疫都是至关重要的。一般而言，疾控中心可以 大致分为两个在功能和发育上截然不同的子集，cDC1和cDC2，它们 分别优先激活CD8T细胞和CD4T细胞。CDC2是表型和功能上的 与cDC2相比，cDC2更具异质性，但不同的cDC2亚群如何获得不同的表型和 人们对其功能仍知之甚少。我们之前已经证明了表达CD301b的小鼠cDC2亚群 (Mgl2)具有独特的功能，在针对过敏原和蠕虫的2型免疫反应中起关键作用。 寄生虫。CD301b+DC存在于几乎所有的外周器官中，并在2型炎症期间扩张，但 它们的分化机制尚不清楚。我们的长期目标是了解CD301b+的机制 树突状细胞在细胞和分子水平的分化及其作为治疗靶点的潜力 患有2型炎症的疾病，如过敏。一般说来，cDC2被认为起源于前 CDC是CDC承诺的循环前体，通过转录因子IRF4的作用。然而，它 目前尚不清楚cDC2中的异质性是起源于它们的前体，还是在 末端分化。同样，虽然IRF4似乎在cDC2的开发中总体上发挥了重要作用， 它在cDC2亚群多样化中的作用仍然难以捉摸，其他因素可能是导致它们 异质性。我们假设前CDC和/或单核细胞获得CD301b+DC表型。 符合IRF4上下文相关要求的上下文相关方式。我们在这项建议中的具体目标是 (1)鉴定在外周器官中产生CD301b+DC的前体细胞群；及(2) 阐明IRF4和CD301b+DC特异性转录因子在它们的分化中的作用 幼稚和受感染的条件。了解cDC2分化的机制可能会给我们提供线索 了解2型过敏症和其他疾病的病因并确定潜在的治疗靶点 发炎。

Project Summary Conventional dendritic cells (cDCs) are crucial for both innate and adaptive immunity. In general, cDCs can be categorized roughly into two functionally and developmentally distinct subsets, cDC1 and cDC2, which preferentially activate CD8T cells and CD4T cells, respectively. cDC2s are phenotypically and functionally more heterogeneous compared to cDC1s, but how different cDC2 subsets acquire distinct phenotype and function remains poorly understood. We previously showed that a mouse cDC2 subset expressing CD301b (Mgl2) is functionally distinct and plays critical role in type 2 immune responses to allergens and helminth parasites. CD301b+ DCs are present in nearly all peripheral organs and expand during type 2 inflammation, but their differentiation mechanism is unknown. Our long-term goal is to understand the mechanism of CD301b+ DC differentiation at the cellular and molecular levels and explore its potential as a therapeutic targets for diseases with type 2 inflammation such as allergies. In general, cDC2s are thought to originate from the pre- cDC, a cDC-committed circulating precursor, through the action of the transcription factor IRF4. However, it remains unclear whether the heterogeneity in cDC2s originates in their precursors, or is acquired later during terminal differentiation. Likewise, while IRF4 seems to play a significant role in cDC2 development in general, its role in diversification of cDC2 subsets remains elusive and additional factors may be responsible for their heterogeneity. We hypothesize that pre-cDCs and/or monocytes acquire the CD301b+ DCs phenotype in a context-dependent manner with context-dependent requirement of IRF4. Our specific aims in this proposal are (1) to identify the precursor cell populations that give rise to CD301b+ DCs in peripheral organs, and (2) to elucidate the role of IRF4 and CD301b+ DC-specific transcription factors in their differentiation, under both naive and infected conditions. Understanding the mechanism of cDC2 differentiation might give us clues to understand the etiology and to identify potential therapeutic targets in allergies and other diseases with type 2 inflammation.