Adipose Tissue Immunosuppressive T Cells Regulate Atherosclerosis Development and Liver Fat Accumulation in Obesity

BACKGROUND: Obesity is associated with a loss of anti-inflammatory regulatory T cells (Tregs) in adipose tissue (AT), resulting in systemic inflammation. The adipocyte is a central modulator of CD4+T-cell subpopulations via antigen presentation through the MHCII (major histocompatibility complex class II). However, the role of adipocyte-induced AT inflammation due to changes in AT Tregs in obesity-related complications, such as atherosclerosis and metabolic-dysfunction-associated fatty liver disease (MAFLD), remains unknown. METHODS: Ldlr (low-density lipoprotein receptor) −/− knockout mice were crossed with adipocyte-specific MHCII knockout (aMHCll [adipocyte MHCII] −/− ) mice to study the effects of AT T-cell changes on atherosclerosis and MAFLD. Metabolic differences, atherosclerotic lesions, liver fat accumulation, and inflammation in adipose, splenic, aortic, and liver tissue were measured in 1-year-old aMHCll −/− Ldlr −/− mice fed a Western high-fat diet for 12 weeks. We used 1-year-old mice because, unlike young mice, they develop markedly accelerated atherosclerosis like humans. RESULTS: Loss of MHCII signaling in adipocytes prevented the obesity-mediated loss of AT Tregs, resulting in decreased insulin resistance, atherosclerosis, and MAFLD. In contrast, depletion of AT Tregs via IL (interleukin)-33 receptor–targeted immunotherapy with ST2 (suppression of tumorigenicity 2) reversed these improvements in Western high-fat diet–fed, 1-year-old aMHCll −/− Ldlr −/− mice, whereas increasing AT Tregs with IL-33 recombinant protein promoted similar beneficial effects as in aMHCll −/− Ldlr −/− mice. Because there were no alterations in splenic Tregs, these differences in atherosclerosis and MAFLD were AT Treg-mediated, independent of peripheral Tregs. Amelioration of insulin resistance, atherosclerosis, and MAFLD was diet- and adipocyte-dependent, as a low-fat, Western diet administered to 1-year-old aMHCll −/− Ldlr −/− mice and myeloid-adipo–specific MHCII knockout mice (m-aMHCll [myeloid-adipocyte MHCII] −/− ) ingesting a Western high-fat diet, had no effect on disease progression. CONCLUSIONS: These results suggest that AT immunosuppressive T cells play a pivotal role in regulating both atherosclerosis development and liver fat accumulation in obesity.