LY9 (lymphocyte antigen 9, also known as CD229 or SLAMF3) is a self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family expressed predominantly on B and T cells 1. As a homophilic adhesion molecule, LY9 regulates lymphocyte activation and differentiation through homo- or heterotypic cell-cell interactions, with activity controlled by adapter proteins SH2D1A/SAP and SH2D1B/EAT-2 2. LY9 promotes T-cell differentiation toward a Th17 phenotype by recruiting RORC to the IL-17 promoter and enhances Th1* cell polarization through SAP-dependent and SAP-independent mechanisms involving T-bet and RORγT 2. Mechanistically, LY9 costimulation enhances TCR-driven IFN-γ production in memory Th1* cells via NFAT1 and RORγT signaling 2. Clinically, autosomal recessive LY9 deficiency causes tuberculosis susceptibility due to selective impairment of Th1*-mediated IFN-γ production 2. LY9 has emerged as a potential therapeutic target in multiple diseases: it is associated with disease progression and disability severity in multiple sclerosis as part of an 11-protein CSF biomarker panel 3, implicated in diabetic retinopathy pathogenesis through immune-inflammatory pathways 4, and identified as a therapeutic candidate in lymphoma with downregulated expression in diffuse large B-cell lymphoma cells 5. Additionally, LY9 variants show rare enrichment in focal segmental glomerulosclerosis 6.