Journal Article

Neuropeptide signalling orchestrates T cell differentiation

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

2024

Overview

The balance between T helper type 1 (T H 1) cells and other T H cells is critical for antiviral and anti-tumour responses 1 – 3 , but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of T H 1 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 T H 1–T H 2 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 T H 1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3–CALCRL restricted the differentiation of T H 2 cells, but promoted T H 1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted T H 1 cell differentiation by inducing the expression of Stat1 , a key regulator of T H 1 cell differentiation. After viral infection, an interaction between CGRP produced by neurons and RAMP3 expressed on T cells enhanced the anti-viral IFNγ-producing T H 1 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 T H 1 cell response. RAMP3, a component of the receptor for the neuropeptide CGRP, has a cell-intrinsic role in T helper type 1 cell fate determination.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2152 / 631/250/2502 / 64/60 / 96 / 96/21 / Activating transcription factor 3 / Activating Transcription Factor 3 - metabolism / Animals / Antiviral agents / Antiviral drugs / Calcitonin / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - metabolism / Calcitonin Receptor-Like Protein - metabolism / CD8 antigen / Cell activation / Cell culture / Cell cycle / Cell Differentiation / Cell fate / COVID-19 / CRISPR / Cyclic AMP response element-binding protein / Cyclic AMP Response Element-Binding Protein - metabolism / Cytokines / Differentiation (biology) / Female / Helper cells / Humanities and Social Sciences / In vivo methods and tests / Infections / Lymphocytes / Lymphocytes T / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Neurons / Neuropeptides / Receptor activity modifying proteins / Receptor Activity-Modifying Protein 3 - metabolism / Receptors / Science / Science (multidisciplinary) / Signal Transduction / Stat1 protein / STAT1 Transcription Factor - metabolism / Th1 Cells - cytology / Th1 Cells - immunology / Th1 Cells - metabolism / Th2 Cells - cytology / Th2 Cells - immunology / Th2 Cells - metabolism / Transcription activation / Transcription factors / Viral infections / γ-Interferon