Neuropeptide signalling orchestrates T cell differentiation

Yu Hou, Linyu Sun, Martin W. LaFleur, Linglin Huang, Conner Lambden, Pratiksha I. Thakore, Kathryn Geiger-Schuller, Kimitoshi Kimura, Longjun Yan, Yue Zang, Ruihan Tang, Jingwen Shi, Rocky Barilla, Liwen Deng, Ayshwarya Subramanian, Antonia Wallrapp, Hee Sun Choi, Yoon-Chul Kye, Orr Ashenberg, Geoffrey Schiebinger, John G. Doench, Isaac M. Chiu, Aviv Regev (), Arlene H. Sharpe () and Vijay K. Kuchroo ()
Additional contact information
Yu Hou: Mass General Hospital and Harvard Medical School
Linyu Sun: Mass General Hospital and Harvard Medical School
Martin W. LaFleur: Mass General Hospital and Harvard Medical School
Linglin Huang: Mass General Hospital and Harvard Medical School
Conner Lambden: Mass General Hospital and Harvard Medical School
Pratiksha I. Thakore: Broad Institute of MIT and Harvard
Kathryn Geiger-Schuller: Broad Institute of MIT and Harvard
Kimitoshi Kimura: Mass General Hospital and Harvard Medical School
Longjun Yan: Zhejiang University School of Medicine
Yue Zang: Zhejiang University School of Medicine
Ruihan Tang: Mass General Hospital and Harvard Medical School
Jingwen Shi: Mass General Hospital and Harvard Medical School
Rocky Barilla: Mass General Hospital and Harvard Medical School
Liwen Deng: Harvard Medical School
Ayshwarya Subramanian: Mass General Hospital and Harvard Medical School
Antonia Wallrapp: Mass General Hospital and Harvard Medical School
Hee Sun Choi: Mass General Hospital and Harvard Medical School
Yoon-Chul Kye: Mass General Hospital and Harvard Medical School
Orr Ashenberg: Broad Institute of MIT and Harvard
Geoffrey Schiebinger: Broad Institute of MIT and Harvard
John G. Doench: Broad Institute of MIT and Harvard
Isaac M. Chiu: Harvard Medical School
Aviv Regev: Broad Institute of MIT and Harvard
Arlene H. Sharpe: Mass General Hospital and Harvard Medical School
Vijay K. Kuchroo: Mass General Hospital and Harvard Medical School

Nature, 2024, vol. 635, issue 8038, 444-452

Abstract: Abstract The balance between T helper type 1 (TH1) cells and other TH cells is critical for antiviral and anti-tumour responses1–3, 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.

Date: 2024
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DOI: 10.1038/s41586-024-08049-w

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