CD22 is the most highly expressed siglec on B cells that plays crucial roles in B-cell biology including differentiation, antigen presentation, and bone marrow trafficking 1. Mechanistically, CD22 functions as an inhibitory coreceptor that binds α2,6-linked sialic acid residues on surface molecules such as CD45, IgM, and CD22 itself in cis configuration, and can also engage ligands on other cells as a trans-acting adhesion molecule 2. CD22 suppresses B-cell receptor signaling through its immunoreceptor tyrosine-based inhibitory motif, which becomes phosphorylated by the Src kinase LYN, recruiting protein tyrosine phosphatase 1/PTPN6 to negatively regulate BCR signaling and inhibit calcium mobilization 3. Sufficiently strong negative signaling can induce B-cell apoptosis 4. Beyond B cells, CD22 is upregulated on aged microglia where it negatively regulates homeostatic phagocytosis; CD22 blockade restores microglial clearance of myelin debris and protein aggregates, improving cognitive function in aged mice 5. CD22 has emerged as a therapeutic target: dual and trispecific CAR-T cells targeting CD22 alongside CD19/CD20 show enhanced efficacy against B-cell malignancies and overcome antigen escape 678. However, CD22 blockade context-dependently exacerbates neuroinflammation in neuromyelitis optica spectrum disorder through enhanced microglial activity 9.