From Adipose Immune Homeostasis to Atherosclerosis and Hepatic Steatosis: The Adipocyte MHCII–Treg Axis in Obesity

Adipocyte MHCII links obesity, adipose tissue inflammation, and whole-body metabolic dysfunction (1).This discovery complements the predictable finding that macrophages have highest MHCII expression in obese adipose tissue (2) with a less expected conclusion: adipocytes function as antigen-presenting cells.Obesity-driven MHCII expression allows murine adipocytes to activate CD4 + T cells and fuel Th1/IFNγ inflammation (1,3; Fig. 1), even while obesity depletes an anti-inflammatory cell type, regulatory T cells (Tregs), in the visceral adipose tissue (VAT) (4,5).Human data mirror these findings by showing that adipocyte MHCII and IFNγ rise as Treg abundance and insulin sensitivity fall in adipose tissue of people with obesity (6).These data indicate that the MHCII-Treg axis in human adipose tissue operates in parallel with systemic T cell inflammation (7-9), while mouse adipose inflammation remains local (4,10).Whether VAT immune dysregulation causes disease beyond local VAT effects in older, Western-diet fed mice is the open question addressed by Blaszczak and colleagues (10).They test the hypothesis that loss of MHCIImediated regulation of VAT Tregs contributes to atherosclerosis and hepatic steatosis.Blaszczak and colleagues (10) put 12-month-old Ldlr-/-mice on a Western diet to model prediabetes.Adipocyte MHCII increased, VAT Tregs decreased, and both atherosclerosis and metabolic dysfunction-associated steatohepatitis (MASH) developed.Knocking out adipocyte MHCII (with macrophage MHCII lost in parallel) led to preservation of VAT Tregs, and atherosclerosis lesions were ~ 50% lower; MASH was also blunted, but body weight, adiposity, and lipids were unaffected (10).Despite limitations of the study that include use of only male mice, and constitutive MHCII deletion (opening the possibility of developmental compensation), the data support the conclusion that the MHCII-knockout effect is due to Treg preservation, rather than a whole-body mass or metabolic effect (10).Subsequent mechanistic approaches showed that antibodies against suppression of tumorigenicity 2 (ST2), which depletes Tregs, erased the protective effects of MHCII knockout, worsening atherosclerosis and MASH (10).Treg expansion through IL-33 treatment improved insulin sensitivity and reduced atherosclerosis without changing peripheral Treg numbers (10).Because both interventions were administered systemically, the authors cannot fully exclude treatment effects on non-VAT Tregs or non-Treg cells.Regardless, the data are consistent with an unexpectedly protective role for VAT Tregs