Aging weakens Th17 cell pathogenicity and ameliorates experimental autoimmune uveitis in mice

He Li,Weiqi Zhang,Wenru Su,Zhaohao Huang,Shuai Ma,Zhaohuai Li,Jie Ren,Binyao Chen,Lei Zhu,Rong Wang,Huyi Feng,Jing Qu,Xiuxing Liu,Si Wang,Lihui Xie,Guang-Hui Liu

doi:10.1007/s13238-021-00882-3

Abstract

Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure. Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process. However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking. We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU). We found extensive and complicated changes in the cellular constituents of CDLNs during aging. When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice. Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice. The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs’ effects on facilitating the pathogenicity of Th17 cells. Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs. Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.

Highlights

With a rapidly expanding elderly population, insights into aging-induced physiological changes will assist in healthy aging
To identify the global gene signatures of cervical draining lymph nodes (CDLNs) cells associated with normal aging, we identified the differentially expressed genes (DEGs) of all cell types identified in CDLNs from old normal mice (ON) and young normal mice (YN) mice and conducted Gene Ontology (GO) analysis of these genes (Fig. 1E, 1F; Table S1A)
We deeply investigate the impact of aging on experimental autoimmune uveitis (EAU)

Summary

Introduction

With a rapidly expanding elderly population, insights into aging-induced physiological changes will assist in healthy aging. The immune system shows marked changes during aging, which are often manifested as compositional and functional alterations in diverse immune cells (Goronzy and Weyand, 2013; Nikolich-Žugich, 2018). Several studies have proposed that older people display greater autoimmunity characterized by increased serum levels of autoantibodies and accumulation of autoreactive T cells due to checkpoint failures during aging (Goronzy and Weyand, 2012; Müller and Pawelec, 2015), the incidence of many autoimmune diseases is lower among the elderly (Cooper and Stroehla, 2003). Most autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis, rarely occur in the elderly and, when they occur, may present with milder symptoms than in younger individuals (Cooper and Stroehla, 2003; Rovenský and Tuchynová, 2008)

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