Neuropeptide signalling orchestrates T cell differentiation

Abstract

The balance between T helper type 1 (T_H1) 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_H1 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_H1-T_H2 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_H1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3-CALCRL restricted the differentiation of T_H2 cells, but promoted T_H1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted T_H1 cell differentiation by inducing the expression of Stat1, a key regulator of T_H1 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_H1 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_H1 cell response.