Fibroblast growth factor receptor 1 as a potential marker of terminal effector peripheral T helper cells in rheumatoid arthritis patients

Abstract

Objectives Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive polyarthritis. CD4+ T cells are pivotal to its pathogenesis, and our previous study revealed the expression of fibroblast growth factor receptor 1 (FGFR1) is modulated by methotrexate treatment in CD4+ T cells of RA patients; however, the roles of FGFR1 in CD4+ T cells in the pathogenesis of RA is unclear. Therefore, in this study, we aimed to characterize FGFR1-positive CD4+ T cells in RA patients. Methods The abundance of FGFR1-positive CD4+ T cells in peripheral blood and synovium was determined. Single-cell RNA sequencing (scRNA-seq) was performed on synovial CD4+ T cells to characterize FGFR1-positive cells. In addition, T cell activation status and cytokine production were determined using flow cytometry. Results The percentage of FGFR1-positive CD4+ T cells in the peripheral blood was higher in RA patients than in healthy controls (P= 0.0035). They were also present in the synovium of active RA patients. The results of scRNA-seq revealed that peripheral T helper (Tph) cells preferentially expressed FGFR1. Additionally, these FGFR1-positive Tph cells displayed a terminal effector cell phenotype. Consistent with this finding, FGFR1-positive CD4+ T cells in peripheral blood expressed interleukin-21 and interferon-γ. Conclusion Our study provides evidence that FGFR1 marks terminal effector Tph cells in patients with RA.

Pathogenic Th17 cells in arthritogenic mice share T cell receptor features with Wild-type Tregs

“…Gene signatures of Th17 Il22 + and Th17 Tnfsf11 + cells were obtained and used for calculation of module scores in scRNAseq datasets of a) Th17 cells obtained from spleens of WT, SKG and ZAC mice (n=2 each), b) CD4 + T cells from inflamed synovia of RA patients (n=3) 27 , c) CD4 + T cells from peripheral blood of RA patients (n=1) 28 , d) CD4 + T cells from synovia and infrapatellar fat pad (IPFP) tissue of osteoarthritis (OA) patients (n=3) 29 , e) Circulating Th17 cells from healthy donors (n=3), and patients with autoimmune diseases other than RA: myasthenia gravis (MG) (n=3), multiple sclerosis (MS) (n=4), systemic lupus erythematosus (SLE) (n=3) 30 .…”

“…To investigate the presence of cells resembling Th17 Tnfsf11 + in human tissues, we calculated Th17 Il22 + and Th17 Tnfsf11 + gene signature module scores in publicly available single-cell RNAseq datasets. We analyzed data obtained from inflamed synovia 27 and PBMCs 28 of RA patients; and, for comparison, we also analyzed data from the synovia and infrapatellar fat pad (IPFP) of osteoarthritis (OA) patients 29 as well as peripheral CD4+ T cells from healthy controls and patients with other autoimmune diseases (myasthenia gravis, multiple sclerosis, and systemic lupus erythematosus) 30 . Detailed descriptions of the datasets are provided in Supplementary Table 7.…”

“…5a). 27 , c) CD4 + T cells from peripheral blood of RA patients (n=1) 28 , d) CD4 + T cells from synovia and infrapatellar fat pad (IPFP) tissue of osteoarthritis (OA) patients (n=3) 29 , e) Circulating Th17 cells from healthy donors (n=3), and patients with autoimmune diseases other than RA: myasthenia gravis (MG) (n=3), multiple sclerosis (MS) (n=4), systemic lupus erythematosus (SLE) (n=3) 30 . [39][40][41][42] .…”

“…CD4 + T cells from RA synovia expressing the Th17 Tnfsfs11 + gene signature are different from Th17.1 or exFoxP3 cells. UMAP plot of CD4 + T cells from inflamed synovia of RA patients (n=3) 27 , cells are colored according to the density of expression of individual markers of Th17.1 ( Ifng , Tbx21 and Cxcr3 ) (a) and exFoxP3 cells ( Sox4 , Ccr6 , Ccl20 , Il23r , and Il17re ) (c) ; or as module scores (b, d) .…”