Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination

Abstract

Dendritic cells have a unique function in the immune response owing to their ability to stimulate immunologically naive T lymphocytes. In response to microbial and inflammatory stimuli, dendritic cells enhance their capacity for antigen presentation by a process of terminal differentiation, termed maturation. The conversion of immature to mature dendritic cells is accompanied by a marked cellular reorganization, including the redistribution of major histocompatibility complex class II molecules (MHC II) from late endosomal and lysosomal compartments to the plasma membrane and the downregulation of some forms of endocytosis, which has been thought to slow the clearance of MHC II from the surface. The relative extent to which these or other mechanisms contribute to the regulation of surface MHC II remains unclear, however. Here we find that the MHC II beta-chain cytoplasmic tail is ubiquitinated in mouse immature dendritic cells. Although only partly required for the sequestration of MHC II in multivesicular bodies, this modification is essential for endocytosis. Notably, ubiquitination of MHC II ceased upon maturation, resulting in the accumulation of MHC II at the cell surface. Dendritic cells thus exhibit a unique ability to regulate MHC II surface expression by selectively controlling MHC II ubiquitination.

Tolerogenicity is not an absolute property of a dendritic cell

“…In contrast to untreated BMDC, all of the modulated populations were impaired to some degree in their ability to upregulate surface expression of these molecules in response to LPS, and this impairment was paralleled by a reduced capacity to stimulate Ag-specific proliferation of naïve T cells in vitro. The E3 ubiquitin ligases MARCH1 and MARCH8 are known to be involved in regulating MHC class II and CD86, with maturationinduced loss of ubiquitination promoting cell surface expression [19][20][21]. Pronounced changes previously reported in the level of MARCH1 mRNA in human monocyte-derived DC, 20-fold on maturation and 40-fold in response to 23], were not evident in our data (Supporting Information Fig.…”

“…1A). Ubiquitination of the cytoplasmic tails of MHC class II and CD86 by MARCH1 and MARCH8 is known to regulate their surface expression [19][20][21]. Transcription of MARCH1 and MARCH8 was, however, essentially unchanged in all of the populations (B6 data not shown).…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…Although the focus in this review has been on how class II gene expression can be regulated at the transcriptional level, it is known that post-transcriptional modifications affecting the cytoplasmic tail of class II molecules may alter their export to the cell surface. 165 Clearly, we still have much more to learn regarding how gene expression is regulated in the class II region. Technological advances should continue to improve our ability to characterize class II expression including, for example, at single cell resolution in vivo, allowing analysis in disease-specific cell types and hopefully unlocking some of the mysteries that have long surrounded MHC class II genetic associations with autoimmune and infectious diseases.…”

Dendritic cells: Understanding immunogenicity

“…Maturation also activated the processing machinery in late endosomes or lysosomes, and allowed for increased formation of peptide-MHC complexes [54]. This was followed by transport of peptide-MHC to the cell surface [55] where degradation was avoided, probably by a newly recognized control in which mature DC turn off ubiquitination of MHC II [56]. Maturation, the differentiation of DC in response to environmental stimuli, is a key to immunogenicity and can involve hundreds of changes in response to signals from microbes, immune complexes, cytokines, innate lymphocytes and a variety of endogenous stimuli currently called "danger signals" or "alarmins".…”