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

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.

Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis

“…Among them, Th17 cells dominate EAU pathogenesis 10 , 11 . Transfer of autoreactive Th17 cells can induce EAU in naïve mice 10 , 12 . In addition, increasing evidence supports the disease-promoting effect of B cells in EAU, although less certain than that of T cells 9 .…”

CD83+ B cells alleviate uveitis through inhibiting DCs by sCD83

“…The expression of CD83 in various cell subsets from lymph nodes of WT and EAU mice was analysed by single-cell sequencing data from previously report [34]. The integrated samples were grouped and defined as 11 cell subpopulations, including precursor T cells (pro-T), CD4 + T cells, CD8 + T cells, Tregs, B cells, plasma cells, neutrophils, monocyte cells, macrophage cells, cDCs and pDCs (Figure S1, left panel).…”

“…The original data of the YN_10 × RNA and YE_10 × RNA groups were downloaded from the CRA004687 dataset of the Genome Sequence Archive (GSA) [34]. ‘CellRanger count’ of cellranger 3.1.0 in Linux Environment was used to analyse multiplex and process the FastQ sequence in the NovaSeq system, and Seurat software (version 2.3.4) was used for filtering, data standardization, dimensionality reduction, clustering, and the single cell expression matrix analyse [35].…”

Mettl3 induced miR‐338‐3p expression in dendritic cells promotes antigen‐specific Th17 cell response via regulation of Dusp16

“…Interleukin‐17 (IL‐17)‐producing T helper (Th17) cells are key pathogenic cells for tissue inflammation and autoimmune diseases, such as uveitis and its animal model experimental autoimmune uveitis (EAU) 1–4 . Dendritic cells (DCs) are major antigen‐presenting cells (APCs) that play a pivotal role in bridging innate and adaptive immunity 5 .…”

“…Interleukin-17 (IL-17)-producing T helper (Th17) cells are key pathogenic cells for tissue inflammation and autoimmune diseases, such as uveitis and its animal model experimental autoimmune uveitis (EAU). [1][2][3][4] Dendritic cells (DCs) are major antigen-presenting cells (APCs) that play a pivotal role in bridging innate and adaptive immunity. 5 On stimulation by antigen, DCs increase the production of proinflammatory cytokines such as IL-6, IL-1β, and IL-23 to direct Th17 cell program.…”