Ly9, also known as CD229 and SLAMF3, is a homophilic receptor belonging to the signaling lymphocytic activation molecule family (SLAMF). It is predominantly expressed on B and T cells, acting as a cosignaling molecule to regulate lymphocyte homeostasis and activation, thus playing crucial roles in innate and adaptive immune responses [1,3].

Ly9 -/- mouse models have revealed multiple functions of Ly9. In iNKT cell development, Ly9 is a non-redundant negative regulator. Ly9-deficient mice on a BALB/c background had an expanded thymic NKT2 cell population and nearly absent NKT1 cells in the thymus, while the number of peripheral NKT1 cells was comparable to wild-type mice, indicating distinct homeostatic requirements for different iNKT cell subsets depending on tissue localization. Also, anti-Ly9 treatment in wild-type mice impaired cytokine production and reduced spleen iNKT cell numbers [2]. In SjS-like disease model (NOD.H-2h4 mice), anti-Ly9 antibody treatment depleted key lymphocyte subsets (MZ, B1, and germinal center B cells) involved in SjS pathology without general immunosuppression, reduced salivary gland lymphocyte infiltration, and decreased anti-nuclear autoantibody levels, suggesting Ly9 as a potential therapeutic target for SjS [4]. Ly9-deficient mice spontaneously developed features of systemic autoimmunity like autoantibody production, and in aged mice, key autoimmunity-related cell subsets were expanded. In vitro, Ly9 acts as an inhibitory receptor of IFN-γ producing CD4(+) T cells [5]. Ly9 -/- T cells show a mild Th2 defect with reduced IL-4 production and poor proliferation and little IL-2 production after suboptimal stimulation, differentiating them from SLAM -/- and SAP -/- mice [6].

In conclusion, Ly9 plays essential roles in lymphocyte homeostasis, iNKT cell development, and the prevention of autoimmunity. Studies using Ly9 -/- mouse models have provided insights into its functions in diseases such as SjS and systemic autoimmunity, highlighting its potential as a therapeutic target in these disease areas.