CARD11, a lymphoid lineage-specific scaffold protein, is crucial for integrating antigen-receptor engagement with downstream signaling to NF-κB and other outputs in lymphocytes [2,4]. It forms the CARD11-BCL10-MALT1 (CBM) signaling complex, which is key in T-and B-cell receptor-induced gene expression by regulating NF-κB activation and mRNA stability [4]. Deregulated CARD11 expression or CBM signaling is associated with immunodeficiency, autoimmunity, and cancer [4]. Mouse models are valuable in studying CARD11 function.

Mouse models with CARD11 and related signaling component deficiencies generally have Treg defects [1]. CARD11 is essential for the development and function of thymic regulatory T cells (Tregs) [1]. Some CARD11-deficient mouse models develop overt autoimmunity and inflammatory disease, while others do not [1]. Also, a germline N-ethyl-N-nitrosourea (ENU)-induced Card11M365K mutation in mice, similar to those in diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphomas (PTCL), increased B and T lymphocyte activation and proliferation following antigen receptor stimulation, and caused over-accumulation of activated T cells, Tregs, T follicular (TFH), and T follicular regulatory (TFR) cells [3].

In conclusion, CARD11 is a key regulator in lymphocyte-mediated immune responses. Its function is essential for Treg development and function, as revealed by mouse models. Dysregulation of CARD11 can lead to various immune-related diseases such as autoimmunity, inflammatory diseases, and lymphoproliferative disorders, highlighting the importance of understanding CARD11 for developing therapies in these disease areas.