WDFY4, also known as WD repeat- and FYVE domain-containing protein 4, is a member of the BEACH (Beige and Chediak-Higashi) domain-containing family. It plays essential roles in the immune system, particularly in the cross-presentation of classic dendritic cells, reactive oxygen species-induced apoptosis of CD8+ T cells, and non-canonical autophagic activity in B cells [3]. Its functions are associated with multiple immune-related pathways and are of great biological importance in the context of immune responses and disease development. Genetic models, such as knockout (KO) mouse models, have been crucial in studying its functions.

In KO mouse models, Wdfy4-/-mice showed normal lymphoid and non-lymphoid cDC1 populations but failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, indicating its requirement for cross-presentation in antiviral and antitumor immunity [1]. In NOD mice, inactivation of Wdfy4 using Nuclease technology led to amelioration of autoimmune diabetes and insulitis, as cDC1s were unable to cross-present cell-associated antigens to prime CD8+ T cells [2]. Lack of Wdfy4 in mice also aggravated ovalbumin-induced asthma via enhanced Th2 cell differentiation [4], reduced the number of CD8+ T cells via reactive oxygen species-induced apoptosis [5], and led to a decrease in total B cells and several B cell subpopulations, alleviating SLE phenotypes [6].

In conclusion, WDFY4 is essential for cross-presentation in the immune response, influencing antiviral, antitumor, and autoimmune disease processes. Gene knockout mouse models have been instrumental in revealing its role in these disease areas, providing insights into the mechanisms underlying immune-related diseases and potentially offering new targets for treatment.