Abstract
Dendritic cells (DCs) are composed of multiple lineages of hematopoietic cells and orchestrate immune responses upon detecting the danger and inflammatory signals associated with pathogen and damaged tissues. Under steady-state, DCs are maintained at limited numbers and the functionally quiescent status. While it is known that a fine balance in the DC homeostasis and activation status is also important to prevent autoimmune diseases and hyperinflammation, mechanisms that control DC development and activation under stead-state remain not fully understood. Here we show that DC-specific ablation of CBL and CBL-B (CBL-/-CBL-B-/-) leads to spontaneous liver inflammation and fibrosis and early death of the mice. The mutant mice have a marked expansion of classic CD8α+/CD103+ DCs (cDC1s) in peripheral lymphoid organs and the liver. These DCs exhibit atypical activation phenotypes characterized by an increased production of inflammatory cytokines and chemokines but not the cell surface MHC-II and costimulatory ligands. While the mutant mice also have massive T cell activation, lymphocytes are not required for the disease development. The CBL-/-CBL-B-/- mutation enhances FLT3-mTOR signaling, due to defective FLT3 ubiquitination and degradation. Blockade of FLT3-mTOR signaling normalizes the homeostasis of cDC1s and attenuates liver inflammation. Our result thus reveals a critical role of CBLs in the maintenance of DC homeostasis and immune quiescence. This regulation could be relevant to liver inflammatory diseases and fibrosis in humans.
Highlights
Dendritic cells (DCs) are special sentinels that orchestrate immune responses against various pathogens and important regulators to control immune tolerance and inflammation [1,2,3]
Flow cytometry analysis revealed that the percentage of CD11c+ MHC-II+ conventional DC (cDC) in the spleen was increased approximately two folds in CBL-/- CBL-B-/- mice compared to WT, CBL-/- or CBLB-/- mice (Figure 1A)
The total number of CD11clow PDCA1+ plasmacytoid DCs (pDC) was not affected by the CBL-/-CBL-B-/- mutation in the bone marrow; they were significantly reduced in the spleen (Supplementary Figures 2C, D)
Summary
Dendritic cells (DCs) are special sentinels that orchestrate immune responses against various pathogens and important regulators to control immune tolerance and inflammation [1,2,3]. It has been reported that increased lifespan of DCs or depletion of DCs may exhibit a profound effect on the immune quiescence and the development of autoimmune and myeloid proliferative diseases [14, 15] These findings suggest that control of a fine balance in DC homeostasis can be another important dimension to maintain DC functional quiescence under steady-state. Our data demonstrate that CBL-mediated protein ubiquitination acts as a critical DC intrinsic regulatory mode to maintain the homeostasis and immune quiescence of peripheral cDCs under steady-state These results suggest a potential role of cDCs in human liver inflammation and fibrosis and that modulation of DC homeostasis could be an effective treatment for liver inflammation and fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
