Mechanism of cDC2 subset differentiation in peripheral organs

项目摘要 传统的树突状细胞（cDC）对于先天性和适应性免疫都是至关重要的。一般来说，cDC可以是 大致分为两个功能和发育不同的子集，cDC 1和cDC 2， 分别优先激活CD 8 T细胞和CD 4 T细胞。cDC 2在表型和功能上 与cDC 1相比更异质，但不同的cDC 2亚群如何获得不同的表型， 功能仍然知之甚少。我们之前的研究表明，表达CD 301 b的小鼠cDC 2亚群 （Mgl 2）在功能上不同，并且在针对过敏原和蠕虫的2型免疫应答中起关键作用 寄生虫CD 301 b + DC几乎存在于所有外周器官中，并在2型炎症期间扩增，但 其分化机制尚不清楚。我们的长期目标是了解CD 301 b+的机制。 DC在细胞和分子水平的分化，并探索其作为治疗靶点的潜力， 2型炎症疾病，如过敏。一般来说，cDC 2被认为起源于前- cDC，一种cDC定向循环前体，通过转录因子IRF 4的作用。但 目前尚不清楚cDC 2的异质性是否起源于其前体，或者是在 终末分化同样，虽然IRF 4似乎在cDC 2的发育中起着重要作用， 它在cDC 2亚群多样化中的作用仍然难以捉摸，另外的因素可能是导致其分化的原因。 异质性我们假设前cDCs和/或单核细胞获得CD 301 b + DCs表型， 上下文相关的方式与IRF 4的上下文相关的要求。我们提出这项建议的具体目的是 (1)鉴定在外周器官中产生CD 301 b + DC的前体细胞群，和（2） 阐明IRF 4和CD 301 b + DC特异性转录因子在其分化中的作用， 幼稚和受感染的条件。了解cDC 2分化的机制可能会给我们提供线索， 了解病因，并确定潜在的治疗目标，在过敏和其他疾病的2型 炎症

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.