Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital and Harvard Medical School, Boston, MA, USA.
Liangzhu Laboratory of Zhejiang University, Zhejiang University School of Medicine, Hangzhou, China.
Nature. 2024 Nov;635(8038):444-452. doi: 10.1038/s41586-024-08049-w. Epub 2024 Oct 16.
The balance between T helper type 1 (T1) cells and other T cells is critical for antiviral and anti-tumour responses, but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of T1 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 T1-T2 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 T1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3-CALCRL restricted the differentiation of T2 cells, but promoted T1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted T1 cell differentiation by inducing the expression of Stat1, a key regulator of T1 cell differentiation. After viral infection, an interaction between CGRP produced by neurons and RAMP3 expressed on T cells enhanced the anti-viral IFNγ-producing T1 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 T1 cell response.
辅助性 T 细胞 1（T1）和其他 T 细胞之间的平衡对于抗病毒和抗肿瘤反应至关重要，但这种平衡是如何实现的仍知之甚少。在这里，我们在体外极化过程中以及急性病毒感染后体内分化过程中解析了 T1 细胞分化的动态调节。我们使用独特的 T1-T2 细胞二分法培养系统来鉴定调节辅助性 T 细胞分化的调节剂，并通过多种体外和体内 CRISPR 筛选系统验证了它们的调节功能。我们发现，RAMP3 是神经肽 CGRP（降钙素基因相关肽）受体的一个组成部分，在 T1 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 T2 细胞的分化，但通过激活下游 cAMP 反应元件结合蛋白（CREB）和激活转录因子 3（ATF3）促进了 T1 细胞的分化。ATF3 通过诱导 Stat1 的表达促进 T1 细胞分化，Stat1 是 T1 细胞分化的关键调节因子。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 IFNγ产生的 T1 和 CD8 T 细胞反应，并及时控制了急性病毒感染。我们的研究确定了一个神经免疫回路，即在急性病毒感染期间，神经元通过产生神经肽 CGRP 参与 T 细胞命运决定，该神经肽作用于表达 RAMP3 的 T 细胞，诱导有效的抗病毒 T1 细胞反应。
