A20 stabilizes IRF8: De novo trogocytic cDC2s orchestrate robust anti-tumor immunity in cDC1-deficient A20cKO mice
Our study explored the role of the ubiquitin-editing enzyme A20 (TNFAIP3) in regulating  conventional dendritic cell (cDC) differentiation and its implications for anti-tumor immunity. We found that A20 stabilizes IRF8, essential for type 1 cDC (cDC1) development, by removing K48-linked polyubiquitin chain. DC-specific A20-depleted (A20cKO) mice showed a significant reduction in cDC1 levels but exhibited robust anti-tumor immunity due to superior MHC-I-mediated antigen presentation by de novo type 2 cDCs (cDC2s). These de novo cDC2s showed distinct gene expression profiles compared to wild-type cDC2s and acquired the ability to trogocytose adjacent tumor cells. NF-?B-dependent TNFa and TBK1/IRF3-mediated type I interferon secreted by cDCs in A20cKO mice played crucial roles in cDC2's acquisition of cross-dressing characteristics, facilitating tumor-specific cytotoxic T lymphocyte responses even when cross-dressed with allo-tumor cells. This study highlights the crucial role of A20 in the development of cDC1s through IRF8 stabilization and unveils the unique anti-tumor potential of A20cKO cDC2s through their cross-dressing capabilities. Overall design: DC1s and DC2s of the WT-BMDC and A20 iKO-BMDC derived from 3 mice each were isolated into using FACS and analyzed using QuantSeq 3' mRNA-Seq.