Composition and function of AChR chimeric autoantibody receptor T cells for antigen-specific B cell depletion in myasthenia gravis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40020066.
- Also identified by DOI 10.1126/sciadv.adt0795 and PMC identifier 11870065.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
In acetylcholine receptor (AChR)-seropositive myasthenia gravis (MG), anti-AChR autoantibodies impair neuromuscular transmission and cause severe muscle weakness. MG therapies broadly suppress immune function, risking infections. We designed a chimeric autoantibody receptor (CAAR) expressing the 210-amino acid extracellular domain of the AChR α subunit (A210) linked to CD137-CD3ζ cytoplasmic domains to direct T cell cytotoxicity against anti-AChRα B cells. A210-CAART incorporating a CD8α transmembrane domain (TMD8α) showed functional but unstable surface expression, partially restored by inhibiting lysosomal degradation. A210-CAART with a CD28 TMD showed sustained surface expression, independent of TMD dimerization motifs. In a mouse xenograft model, A210.TMD8α-CAART demonstrated early control of anti-AChR B cell outgrowth but subsequent rebound and loss of surface CAAR expression, whereas A210.TMD28-CAART induced sustained surface CAAR expression and target cell elimination. This study demonstrates the importance of the CD28 TMD for CAAR stability and in vivo function, laying the groundwork for future development of precision cellular immunotherapy for AChR-MG.
Medical subject headings
- B-Lymphocytes
- Receptors, Cholinergic
- Myasthenia Gravis
- Autoantibodies
- T-Lymphocytes
- Lymphocyte Depletion