Lack of the E3 Ubiquitin Ligase March1 Affects CD8 T Cell Fate and Exacerbates Insulin Resistance in Obese Mice.

Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. However, the mechanisms that trigger the underlying adipose tissues inflammation are not completely understood. Here, we show that the E3 ubiquitin ligase March1 controls the phenotypic and functional properties of CD8+ T cells in mice white adipose tissue. In a diet-induced obesity model, mice lacking March1 [March1 knockout (KO)] show increased insulin resistance compared to their WT counterparts. Also, in obese March1 KO mice, the proportions of effector/memory (Tem) and resident/memory (Trm) CD8+ T cells were higher in the visceral adipose tissue, but not in the spleen. The effect of March1 on insulin resistance and on the phenotype of adipose tissue CD8+ T cells was independent of major histocompatibility complex class II ubiquitination. Interestingly, we adoptively transferred either WT or March1 KO splenic CD8+ T cells into obese WT chimeras that had been reconstituted with Rag1-deficient bone marrow. We observed an enrichment of Tem and Trm cells and exacerbated insulin resistance in mice that received March1 KO CD8 T cells. Mechanistically, we found that March1 deficiency alters the metabolic activity of CD8+ T cells. Our results provide additional evidence of the involvement of CD8+ T cells in adipose tissue inflammation and suggest that March1 controls the metabolic reprogramming of these cells.

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

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.

On the structure-function of MHC class II molecules and how single amino acid polymorphisms could alter intracellular trafficking.

Classical HLA class II molecules are highly polymorphic heterodimeric transmembrane proteins encoded by a polygenic cluster on chromosome 6. Polymorphic residues in the membrane-distal domains ensure that a large collection of microbial peptides can be bound in the human population. Still, the HLA-DR, -DP and -DQ isotypes show a high degree of conservation in their overall tertiary and quaternary structures, in line with their common function in T cell receptor activation. Interestingly, the primary structure of the intracellular domains are highly divergent between isotypes and they also show allotypic variations. The functional impact of these differences remains to be fully appreciated. Here, we address the role of the MHC class II cytoplasmic tails in intracellular trafficking. First, the emphasis will be on the interplay between the cytoplasmic domains of classical human MHC class II molecules and those of the invariant chain chaperone (CD74) isoforms. Then, we will examine the importance of the highly conserved ß-chain cytoplasmic lysine residue in the ubiquitin-driven trafficking of MHC class II molecules. These considerations should help understand the potential functional impact of sequence variations that may arise in the cytoplasmic tails and transmembrane domains of MHC class II molecules.