Abstract
Type 2 diabetes (T2D) is a complex metabolic disorder driven by chronic inflammation and immune dysregulation, particularly within adipose tissue. This study investigates the role of the T cell-specific protein Themis in modulating immune-metabolic interactions that contribute to T2D pathogenesis. Using high-fat diet (HFD)-induced obesity models, we demonstrate that Themis-deficient (KO) mice exhibit accelerated weight gain, glucose intolerance, and insulin resistance compared to wild-type (WT) controls. These metabolic abnormalities are linked to functional alterations in the CD8(+) T cell compartment, including site-specific clonal expansion and reshaping of the T cell receptor (TCR) repertoire within adipose tissue, suggesting antigen-driven activation. Additionally, Themis deficiency leads to significant shifts in gut microbiome composition, characterized by reduced diversity and increased abundance of Firmicutes, particularly Clostridium species. However, fecal microbiota transplantation from Themis KO mice into germ-free WT hosts failed to recapitulate the full T2D phenotype, underscoring the dominant role of intrinsic immune dysfunction over microbial dysbiosis. These findings highlight a synergistic interplay between adaptive immunity and the microbiome in shaping metabolic outcomes and suggest that T cells play a central role in responses that influence T2D progression. Our data advocate for a more integrated approach to T2D research, incorporating genetic, immunological, and microbial factors.