Cd226, also known as DNAM-1, is a costimulatory molecule that plays a crucial role in the immune system. It is involved in various pathways, competing with inhibitory receptors like TIGIT and CD96 to bind ligands such as CD155 on the surface of tumor cells. This competition mediates the killing function of NK cells and regulates the activity of T cells, thereby participating in anti-tumor immunity and immune cell function regulation [1,2,3,6].

In murine graft-versus-host disease models, conditional deletion of CD226 within Foxp3+ cells exacerbates symptoms. Treg cell-specific deletion of CD226 increases the Treg cell percentage in immune organs but weakens their immunosuppressive function, with a T helper 1-like phenotype conversion under inflammation. CD226-deficient Treg cells show reduced oxidative phosphorylation and increased glycolysis rates, regulated by the AMPK/mTOR/Myc pathway [4]. In cyclophosphamide-induced and streptozotocin-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity [5]. CD4+ T cell-specific Cd226-knockout mice challenged with ovalbumin show mitigated lung inflammation, IgE production, and eosinophil infiltration, and reduced airway remodeling in experimental allergic asthma [7]. Anti-TIGIT treatment selectively affects CD226hiCD8+ T cells, and CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8+ T-cell responses [8].

In conclusion, Cd226 is essential for maintaining the phenotype stability and metabolism of regulatory T cells, regulating the progression of type 1 diabetes, contributing to asthmatic pathogenesis, and playing a role in anti-TIGIT immunotherapy. Gene knockout and conditional knockout mouse models have been instrumental in revealing these functions of Cd226 in different disease areas, providing potential therapeutic targets for inflammatory diseases, diabetes, asthma, and cancer immunotherapy.