ANKRD55 is a key regulator of T cell inflammation in multiple sclerosis
Chuyu Wu, Meiling Jiang, Xue Yang, Yixuan Liu, Bin Huang, Yi Guo, Runjing Cao, Zhihui Cui, Guozhen Deng, Weiyan Wang, Mengdi Guo, Zhiyong Lin, Jiahui Fan, Lin-ming Zhang, Lorenzo Di Cesare Mannelli, Tao Pang, Chenhui Wang, Cun-Jin Zhang
Chuyu Wu, Meiling Jiang, Xue Yang, Yixuan Liu, Bin Huang, Yi Guo, Runjing Cao, Zhihui Cui, Guozhen Deng, Weiyan Wang, Mengdi Guo, Zhiyong Lin, Jiahui Fan, Lin-ming Zhang, Lorenzo Di Cesare Mannelli, Tao Pang, Chenhui Wang, Cun-Jin Zhang
View: Text | PDF
Research Article Autoimmunity Immunology

ANKRD55 is a key regulator of T cell inflammation in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a progressive, chronic, and highly disabling neuroinflammatory disorder characterized by demyelination and T cell–driven inflammation. Pathogenic T cells play a central role in MS, but effective therapeutic targeting remains challenging. Here, we identified ankyrin repeat domain–containing protein 55 (ANKRD55) as a key regulator of T cell function by single-cell transcriptomic analysis of cerebrospinal fluid and blood from MS patients. ANKRD55 was predominantly expressed in CD4+ T cells in both compartments. Genetic ablation of Ankrd55 led to a robustly reduced disease severity and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Furthermore, T cell–specific deficiency of Ankrd55 significantly impaired Th1 polarization and Th17 differentiation, reducing EAE pathogenicity. Mechanistically, we found that Ankrd55 deficiency disrupted T cell receptor (TCR) signaling integrity. We demonstrated that ANKRD55 regulates the formation of the immune synapse, an essential prerequisite for TCR activation, by interacting with subunits of the chaperonin-containing TCP1 (CCT) complex and modulating its activity, enhancing its assembly by competing with CCT5 for binding to TCP1, CCT3, and CCT6. This facilitates proper microtubule organization and TCR activation. These findings establish ANKRD55 as a critical regulator of TCR signaling and highlight its therapeutic potential in pathogenic T cell–driven autoimmune diseases.

Authors

Chuyu Wu, Meiling Jiang, Xue Yang, Yixuan Liu, Bin Huang, Yi Guo, Runjing Cao, Zhihui Cui, Guozhen Deng, Weiyan Wang, Mengdi Guo, Zhiyong Lin, Jiahui Fan, Lin-ming Zhang, Lorenzo Di Cesare Mannelli, Tao Pang, Chenhui Wang, Cun-Jin Zhang

×

Figure 1

ANKRD55 promotes disease progression of MOG35–55-induced EAE.

Options: View larger image (or click on image) Download as PowerPoint
ANKRD55 promotes disease progression of MOG35–55-induced EAE. (A) Pseudo...
(A) Pseudo-bulk analysis of ANKRD55 expression in CSF cells from healthy controls (HC) and MS patients; each dot represents an individual sample. (B) The expression level of ANKRD55 was measured at single-cell resolution in diverse cells within CSF samples; each dot represents one cell. (C) Immunoblot analysis was performed to compare ANKRD55 expression between PBMCs from healthy human control subjects and MS patients. (D–G) Immunoblot analysis of ANKRD55 in spleen (D) and lymph node (E) of naive and EAE mice. Densitometric quantification of band intensities was performed using ImageJ, and protein expression levels were normalized to GAPDH (F and G). (H) The mean clinical score of EAE was assessed in WT and Ankrd55–/– mice (n = 11 mice per group) following active immunization with MOG35–55 peptide. (I and J) Infiltrated immune cells in the brain were analyzed by flow cytometry in WT and Ankrd55–/– mice at the peak of EAE disease. Data are presented as representative plots (I) and quantification of cells in the CNS (J). (K) Quantitative analysis of inflammatory cytokine and chemokine expression in the spinal cords of WT and Ankrd55–/– mice at the peak of EAE. (L) Representative histological images of spinal cord sections from WT and Ankrd55–/– mice at peak disease. LFB, Luxol fast blue. Scale bars: 200 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, based on unpaired, 2-tailed t test (A, C, F, G, J, and K) or 2-way ANOVA with Tukey’s multiple-comparison test (H). Data are shown as mean ± SEM.