Spatial microenvironments tune immune response dynamics in the Drosophila larval fat body

Brandon H. Schlomann, Ting-Wei Pai, Jazmin Sandhu, Genesis Ferrer Imbert, Thomas G.W. Graham, Hernan G Garcia
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Abstract

Immune responses in tissues display intricate patterns of gene expression that vary across space and time. While such patterns have been increasingly linked to disease outcomes, the mechanisms that generate them and the logic behind them remain poorly understood. As a tractable model of spatial immune responses, we investigated heterogeneous expression of antimicrobial peptides in the larval fly fat body, an organ functionally analogous to the liver. To capture the dynamics of immune response across the full tissue at single-cell resolution, we established live light sheet fluorescence microscopy of whole larvae. We discovered that expression of antimicrobial peptides occurs in a reproducible spatial pattern, with enhanced expression in the anterior and posterior lobes of the fat body. This pattern correlates with microbial localization via blood flow but is not caused by it: loss of heartbeat suppresses microbial transport but leaves the expression pattern unchanged. This result suggests that regions of the tissue most likely to encounter microbes via blood flow are primed to produce antimicrobials. Spatial transcriptomics revealed that these immune microenvironments are defined by genes spanning multiple biological processes, including lipid-binding proteins that regulate host cell death by the immune system. In sum, the larval fly fat body exhibits spatial compartmentalization of immune activity that resembles the strategic positioning of immune cells in mammals, such as in the liver, gut, and lymph nodes. This finding suggests that tissues may share a conserved spatial organization that optimizes immune responses for antimicrobial efficacy while preventing excessive self-damage.
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空间微环境调节果蝇幼虫脂肪体的免疫反应动态
组织中的免疫反应显示出复杂的基因表达模式,这些模式在不同的空间和时间各不相同。虽然这种模式越来越多地与疾病结果联系在一起,但人们对产生这种模式的机制及其背后的逻辑仍然知之甚少。作为空间免疫反应的一个可行模型,我们研究了幼蝇脂肪体中抗菌肽的异质性表达,脂肪体是一个在功能上类似于肝脏的器官。为了以单细胞分辨率捕捉整个组织的免疫反应动态,我们建立了整个幼虫的活体光片荧光显微镜。我们发现,抗菌肽的表达具有可重现的空间模式,在脂肪体的前叶和后叶表达增强。这种模式与微生物通过血流定位有关,但并非由血流引起:失去心跳会抑制微生物的运输,但表达模式不会改变。这一结果表明,组织中最有可能通过血流与微生物相遇的区域已开始产生抗菌素。空间转录组学发现,这些免疫微环境是由跨越多个生物过程的基因定义的,其中包括调节免疫系统导致宿主细胞死亡的脂质结合蛋白。总之,幼蝇脂肪体表现出免疫活动的空间分区,类似于哺乳动物免疫细胞的战略定位,如肝脏、肠道和淋巴结。这一发现表明,各组织可能共享一种保守的空间组织,这种组织既能优化免疫反应以提高抗菌效力,又能防止过度的自我损伤。
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