美国麻省总医院Vijay K. Kuchroo等研究人员合作发现，神经肽信号调控T细胞分化。相关论文于2024年10月16日在线发表在《自然》杂志上。

研究人员分析了T辅助细胞1型（T_H1细胞）细胞在体外极化过程中以及急性病毒感染后体内分化的动态调控。研究人员使用独特的T_H1-T_H2细胞二分培养系统鉴定了调节T辅助细胞分化的调控因子，并通过多次体外和体内的CRISPR筛选系统地验证了它们的调节功能。

研究人员发现，RAMP3作为神经肽CGRP（降钙素基因相关肽）受体的组成部分，在T_H1细胞命运决定中具有细胞内在作用。通过受体RAMP3-CALCRL的细胞外CGRP信号限制了T_H2细胞的分化，但通过激活下游的cAMP反应元件结合蛋白（CREB）和激活转录因子3（ATF3）促进了T_H1细胞的分化。

ATF3通过诱导T_H1细胞分化的关键调节因子Stat1的表达，促进了T_H1细胞的分化。在病毒感染后，神经元产生的CGRP与T细胞上表达的RAMP3之间的相互作用增强了抗病毒的IFNγ产生的T_H1和CD8⁺ T细胞反应，并及时控制了急性病毒感染。

该研究揭示了一种神经免疫回路，神经元在急性病毒感染期间通过产生神经肽CGRP参与T细胞命运决定，CGRP作用于表达RAMP3的T细胞以诱导有效的抗病毒T_H1细胞反应。

据介绍，TH1细胞与其他TH细胞之间的平衡对于抗病毒和抗肿瘤反应至关重要，但这一平衡是如何实现的仍然知之甚少。

附：英文原文

Title: Neuropeptide signalling orchestrates T cell differentiation

Author: Hou, Yu, Sun, Linyu, LaFleur, Martin W., Huang, Linglin, Lambden, Conner, Thakore, Pratiksha I., Geiger-Schuller, Kathryn, Kimura, Kimitoshi, Yan, Longjun, Zang, Yue, Tang, Ruihan, Shi, Jingwen, Barilla, Rocky, Deng, Liwen, Subramanian, Ayshwarya, Wallrapp, Antonia, Choi, Hee Sun, Kye, Yoon-Chul, Ashenberg, Orr, Schiebinger, Geoffrey, Doench, John G., Chiu, Isaac M., Regev, Aviv, Sharpe, Arlene H., Kuchroo, Vijay K.

Issue&Volume: 2024-10-16

Abstract: The balance between T helper type 1 (TH1) cells and other TH cells is critical for antiviral and anti-tumour responses1,2,3, but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of TH1 cell differentiation during in vitro polarization, and during in vivo differentiation after acute viral infection. We identified regulators modulating T helper cell differentiation using a unique TH1–TH2 cell dichotomous culture system and systematically validated their regulatory functions through multiple in vitro and in vivo CRISPR screens. We found that RAMP3, a component of the receptor for the neuropeptide CGRP (calcitonin gene-related peptide), has a cell-intrinsic role in TH1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3–CALCRL restricted the differentiation of TH2 cells, but promoted TH1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted TH1 cell differentiation by inducing the expression of Stat1, a key regulator of TH1 cell differentiation. After viral infection, an interaction between CGRP produced by neurons and RAMP3 expressed on T cells enhanced the anti-viral IFNγ-producing TH1 and CD8+ T cell response, and timely control of acute viral infection. Our research identifies a neuroimmune circuit in which neurons participate in T cell fate determination by producing the neuropeptide CGRP during acute viral infection, which acts on RAMP3-expressing T cells to induce an effective anti-viral TH1 cell response.

DOI: 10.1038/s41586-024-08049-w

Source: https://www.nature.com/articles/s41586-024-08049-w