Cblb, short for Casitas B-lineage lymphoma proto-oncogene B, is an E3 ubiquitin ligase. It plays a key role in downregulating positive signaling cascades by ubiquitinating proteins downstream of immune receptors. Cblb is involved in regulating both innate and adaptive immune cells, and is part of pathways such as CD28 and CTLA-4 signaling [3,6]. Genetic models, like gene knockout mouse models, have been crucial in understanding its functions.

In gene knockout models, Cblb-deficient CD8+ T cells show resistance to regulatory T cells, accompanied by IFNγ induction and down-modulation of TGFβ/SMAD signaling, making them more effective against cancers [2]. In CD4+ T cells, Cblb deficiency leads to hyperproliferation, excessive IL-2 production, and resistance to Treg suppression, overcoming Treg-mediated inhibition at transcriptional and translational levels [4]. Cblb-deficient mice also develop hyper T follicular helper (Tfh) cell responses and lupus due to reduced BCL6 degradation [1]. In addition, homozygous mutations in Cblb in mice cause T and B cell hyperproliferation, and T effector cells are resistant to WT Treg suppression [6]. Ablation of Cblb in human placental stem cell-derived NK cells enhances their cytotoxicity against tumors [5].

In conclusion, Cblb is a significant regulator in the immune system. Through gene knockout mouse models, its role in immune-related diseases such as autoimmunity, lupus, and cancer has been revealed. These findings suggest that targeting Cblb could be a potential therapeutic strategy for these diseases.