美国加州大学圣迭戈分校Ananda W. Goldrath等研究人员合作发现，组织驻留记忆CD8 T细胞的多样性在时空上受到印记。这一研究成果于2025年1月22日在线发表在国际学术期刊《自然》上。

研究人员提出，不同的组织微环境驱动了组织驻留记忆CD8 T细胞（T_RM细胞）的表型异质性。为了验证这一假设，研究人员利用人类样本的空间转录组学、小鼠急性系统性病毒感染模型以及一种新建立的用于群体光学编码基因干扰策略，在单转录本分辨率下，探讨了病原特异性T_RM细胞分化的位置、相互作用和转录组。研究人员开发了计算方法，以捕捉小肠三个解剖轴上的细胞位置，并可视化细胞类型和基因表达的时空分布。

研究揭示，小肠结构的区域性信号传导支持两种不同的T_RM细胞状态：分化的T_RM细胞和类祖细胞T_RM细胞，分别位于上绒毛和下绒毛。这种多样性是通过不同的配体-受体活动、细胞因子梯度和特化的细胞接触介导的。通过阻断抗原特异性CD8 T细胞的TGFβ或CXCL9、CXCL10感知，研究人员提出了一种与解剖学上划定的早期命运指定一致的模型。最终，研究人员为研究组织免疫网络提供的框架揭示了T细胞的位置和功能状态是密切相关的。

据了解，T_RM细胞在屏障部位提供感染保护。在小肠中，T_RM细胞至少分为两种不同的亚群：一种具有较高的效应分子表达，另一种则具有更强的记忆潜力。然而，这种多样性的起源仍然未知。

附：英文原文

Title: Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted

Author: Reina-Campos, Miguel, Monell, Alexander, Ferry, Amir, Luna, Vida, Cheung, Kitty P., Galletti, Giovanni, Scharping, Nicole E., Takehara, Kennidy K., Quon, Sara, Challita, Peter P., Boland, Brigid, Lin, Yun Hsuan, Wong, William H., Indralingam, Cynthia S., Neadeau, Hayley, Alarcn, Suzie, Yeo, Gene W., Chang, John T., Heeg, Maximilian, Goldrath, Ananda W.

Issue&Volume: 2025-01-22

Abstract: Tissue-resident memory CD8 T (TRM) cells provide protection from infection at barrier sites. In the small intestine, TRM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential1. However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of TRM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct TRM cell states: differentiated TRM cells and progenitor-like TRM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand–receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.

DOI: 10.1038/s41586-024-08466-x

Source: https://www.nature.com/articles/s41586-024-08466-x