可逆性CD8 T细胞与神经元的相互作用导致衰老依赖性神经元再生能力下降。

Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline.

作者信息

Zhou Luming, Kong Guiping, Palmisano Ilaria, Cencioni Maria Teresa, Danzi Matt, De Virgiliis Francesco, Chadwick Jessica S, Crawford Greg, Yu Zicheng, De Winter Fred, Lemmon Vance, Bixby John, Puttagunta Radhika, Verhaagen Joost, Pospori Constandina, Lo Celso Cristina, Strid Jessica, Botto Marina, Di Giovanni Simone

机构信息

Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.

Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK.

出版信息

Science. 2022 May 13;376(6594):eabd5926. doi: 10.1126/science.abd5926.

DOI:10.1126/science.abd5926

PMID:35549409

Abstract

Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice. Lymphotoxin activated the transcription factor NF-κB, which induced expression of the chemokine CXCL13 by neurons. This in turn recruited CXCR5CD8 T cells to injured DRG neurons overexpressing major histocompatibility complex class I. CD8 T cells repressed the axonal regeneration of DRG neurons via caspase 3 activation. CXCL13 neutralization prevented CXCR5CD8 T cell recruitment to the DRG and reversed aging-dependent regenerative decline, thereby promoting neurological recovery after SNI. Thus, axonal regeneration can be facilitated by antagonizing cross-talk between immune cells and neurons.

摘要

衰老与轴突损伤患病率增加相关，其特征为再生能力差和功能障碍。然而，潜在机制仍不清楚。在我们的实验中，对小鼠坐骨背根神经节（DRG）进行RNA测序发现，在坐骨神经损伤（SNI）前后，T细胞信号传导均存在显著的衰老依赖性富集。淋巴毒素激活转录因子NF-κB，后者诱导神经元表达趋化因子CXCL13。这反过来又将CXCR5⁺ CD8⁺ T细胞招募到过表达主要组织相容性复合体I类的损伤DRG神经元处。CD8⁺ T细胞通过激活半胱天冬酶3抑制DRG神经元的轴突再生。中和CXCL13可防止CXCR5⁺ CD8⁺ T细胞募集到DRG，并逆转衰老依赖性的再生能力下降，从而促进SNI后的神经功能恢复。因此，通过拮抗免疫细胞与神经元之间的相互作用，可以促进轴突再生。