Neuropeptide signalling orchestrates T cell differentiation

• Published in: Nature (London) Vol. 635; no. 8038; pp. 444 - 452
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2024; Nature Publishing Group
• Subjects: 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
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08049-w

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.