Obesity, characterized by chronic inflammation and systemic dyshomeostasis, profoundly impacts immune function. This thesis examines how obesity and high-fat diets (HFD) reshape immune responses, with a particular focus on T cell function and inflammatory diseases like psoriasis. Chapter 1, a comprehensive review, explores how obesity and HFD alter immune function in contexts such as microbial defense, inflammatory diseases, and antitumor immunity, emphasizing the role of T cells in adipose tissue and the broader impact of metabolism on immune homeostasis.
Chapters 2 and 3 present original research that investigate the mechanisms of HFD-induced immune dysregulation. Chapter 2 demonstrates that short-term HFD significantly worsens disease severity in a model of experimental psoriasis, identifying a critical 4-day window during disease onset in which NLRP3 inflammasome activation drives TH17 cellular differentiation via IL-1R1 signaling. This transient HFD exposure has long-term consequences, predisposing to more severe flares during subsequent disease episodes, a process mediated by CD4+ T cells.
In Chapter 3, we examine the pathways disrupted by obesity and HFD feeding. Diet-induced obesity is known to impair PPARγ signaling in CD4+ T cells, which has been linked to altered immune responses in skin inflammatory diseases. Here, we demonstrate that PDK4 is a direct target of PPARγ in CD4+ T cells, playing a key role in modulating TH17 cell-driven inflammation, particularly in psoriasis. T-cell specific PDK4 deficiency leads to heightened skin inflammation, and rosiglitazone-mediated PPARγ activation protects against HFD-induced inflammation, a protection lost in T-cell specific PDK4-deficient mice. Collectively, these findings highlight the critical role of PDK4 in T cell function and offer new therapeutic insights for managing diet-induced inflammation.