Downregulation of MHC Class II by Ubiquitination Is Required for the Migration of CD206+ Dendritic Cells to Skin-Draining Lymph Nodes

Abstract

Dendritic cells (DCs) are critical players in skin homeostasis. A subset of mannose receptor (CD206)-expressing monocyte-derived DCs was found in skin, and their migratory counterpart is present in skin-draining lymph nodes (sdLNs). Skin CD206 + DCs were shown to upregulate MHC class II (MHCII) progressively, raising the question of whether this feature affects their biology. In this study, we assessed the role of MHCII regulation in the development and migration of these cells in mouse models expressing differential MHCII levels. Using CD206 as a surrogate marker, we found that skin CD206 + DCs develop in an MHCII-independent manner. However, their migration to sdLNs was affected by overexpression rather than absence or lower expression of MHCII. Accordingly, B16 tumor growth was exacerbated in mice overexpressing MHCII in the absence of ubiquitination. Mechanistically, CD206 + DCs from these mice showed decreased IRF4 and CCR7 expression. LPS, which is known to promote monocyte-derived DC recruitment to sdLNs, partially improved these defects. However, GM-CSF delivery restored CD206 + DC migration by promoting IRF4 expression. Collectively, these data show that MHCII downregulation is crucial for IRF4-dependent migration of CD206 + DCs to sdLNs in health and disease.

Ubiquitination of MHC Class II by March-I Regulates Dendritic Cell Fitness

“…Despite this unremarkable role for ubiquitination in regulating the cell biology of MHC-II expression, studies have attributed MHC-II turnover to a wide variety of immunological phenomena in MHC-II ubiquitination-deficient mice, including modulation of regulatory T cell generation (12,13), affinity maturation in germinal centers (9), DnaK-induced alloimmunity (31), MHC class I expression and function on DCs (32), and migration of CD206 + DCs to skin-draining lymph nodes (14). Incubation of MHC-II ubiquitination-deficient DCs with specific Ags ex vivo enhances expression of Ag-specific pMHC-II (2,12), a phenomenon that has been proposed to reflect enhanced Ag presentation by these cells in vivo (12).…”

“…A number of recent studies have analyzed APC function in MHC-II K 225 R and March-I knockout (KO) mice, and the overall conclusion from these studies is that pMHC-II turnover, regulated by ubiquitination by March-I, is an important regulator of APC function (12)(13)(14). In this study, we address the issue of DC "fitness" in MHC-II ubiquitination-mutant mice by analyzing in detail MHC-II K 225 R and March-I KO DCs isolated from mice of a variety of genetic backgrounds, in mixed bone marrow (BM) chimeras, and in F1 breeding of wildtype (WT) and MHC-II K 225 R mice.…”

Roles of Ubiquitination and Deubiquitination in Regulating Dendritic Cell Maturation and Function

“…The migratory ability of DCs is key for the initiation of protective pro-inflammatory and tolerogenic immune responses ( 72 ). Apart from glycolytic metabolism and epigenetic pathways ( 73 , 74 ), ubiquitination is also involved in the regulation of the migration of different DC subsets in health and disease ( 27 , 45 ). A CRL5 complex, Cullin RING Ligase CRL5 ASB2α, which is highly expressed in immature DCs and down-regulated following DC maturation, which promotes DC migration by facilitating cell spreading and the formation of adhesive structures in immature DCs.…”

“…Further research reveals that CRL5 ASB2α triggers polyubiquitylation and drives proteasome-mediated degradation of actin-binding protein filamins (FLNs), which are major organizers of the actin cytoskeleton ( 45 ). Interestingly, MARCH1-mediated MHCII ubiquitination is essential for the antigen presentation function of DCs but is also required for the migration of CD206-expressing monocyte-derived DCs (CD206 + MoDCs) to skin-draining lymph nodes (sdLNs) ( 27 ). The expression of IFN regulatory factor (IRF) 4 and C-C Motif Chemokine Receptor 7 (CCR7) play a pivotal role in controlling DC migration ( 72 ).…”