2. Academic Validation
  3. ANKRD55 is a key regulator of T cell inflammation in multiple sclerosis

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

  • J Clin Invest. 2025 Oct 15;135(20):e195214. doi: 10.1172/JCI195214.
Chuyu Wu 1,  Meiling Jiang 2,  Xue Yang 1,  Yixuan Liu 1,  Bin Huang 1,  Yi Guo 1,  Runjing Cao 3,  Zhihui Cui 4 5 6,  Guozhen Deng 1,  Weiyan Wang 1,  Mengdi Guo 1,  Zhiyong Lin 1,  Jiahui Fan 1,  Lin-Ming Zhang 7,  Lorenzo Di Cesare Mannelli 8,  Tao Pang 9,  Chenhui Wang 4 5 6,  Cun-Jin Zhang 1
Affiliations

Affiliations

  • 1 Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
  • 2 Department of Science and Technology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 3 Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
  • 4 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 5 Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
  • 6 Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China.
  • 7 Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 8 Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
  • 9 State Key Laboratory of Natural Medicines, New Drug Screening and Pharmacodynamics Evaluation Center, Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing, China.
PMID: 41090353 DOI: 10.1172/JCI195214
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.

Keywords

Autoimmune diseases; Autoimmunity; Immunology; Multiple sclerosis; T cell receptor.

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