Work

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

Year: 2025

Type: article

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.

Source: Journal of Clinical Investigation

DOI: 10.1172/jci195214