Obesity is a global health problem that confers a paradoxical state of both systemic inflammation and impaired immune response. The mechanisms responsible for this immune dysfunction are unclear and this gap in knowledge limits therapeutic interventions. The long-term goal of our research is to understand the molecular regulation and functional consequences of T cell homeostasis in normal development and disease states. The objective of this application is to determine how T cell homeostatic proliferation and functional capabilities are altered in obesity. Based on our preliminary findings we propose that both the reduced response to infection and the initiation of the inflammatory state in obesity result from augmented T cell homeostatic proliferation. In obesity, the expanding adipose tissue mass, combined with elevated IL-7, drive a compensatory increase in T cell homeostatic proliferation in order maintain the growing T cell compartment. Increased T cell homeostatic expansion yields T cells that could be detrimental to immune responses, as a result of their expression of inhibitory proteins (PD-1, Lag3, IL-10), and yet also contribute to chronic inflammation due to the upregulation of FasL and granzyme B. This is particularly important in adipose tissue where infiltrating CD8+ T cells have been implicated in the initiation and propagation of inflammation, yet the source and function of these CD8+ T cells has not been described. We further hypothesize that CD8+ T cells that have upregulated FasL as a consequence of homeostatic expansion stimulate Fas-expressing adipocytes to secrete proinflammatory cytokines and possibly induce adipocyte death, and thus have a pivotal role in the initiation of inflammation. These studies will advance our understanding of T cell homeostasis and function in obesity and the mechanisms that contribute to the paradox of poor immune response in the context of inflammation. These data will also provide new insight into the initiation of adipose tissue inflammation that drives many of the comorbidities seen in obese patients. This knowledge should identify potential avenues for immunotherapy to prevent inflammation and improve T cell function in obese patients that would significantly improve human health.
The specific aims of this proposal are:
Aim 1 : Determine how T cell homeostatic proliferation and phenotype are affected by obesity. We hypothesize that T cell homeostatic proliferation, measured by in vivo BrdU incorporation, will be elevated in obese mice resulting in an increase in CD44highCD8+ T cells that express PD- 1, Lag3, and FasL.
Aim 2 : Determine how CD8+ T cells that have undergone homeostatic proliferation contribute to the initiation of the inflammatory cascade in adipose tissue. We hypothesize that FasL expressed by CD8+ T cells that have undergone homeostatic expansion will stimulate adipocytes to secrete inflammatory cytokines and possibly induce adipocyte death. This will be tested both in vitro and in vivo.
Obesity is an epidemic global health problem that is associated with numerous comorbidities that negatively affect human health and life expectancy and have substantial economic and societal costs. The goal of these studies is to understand how the obese environment alters T cell homeostasis and function and how these changes contribute to both the impaired T cell responses and chronic inflammation observed in obesity. This work has the potential to lead to novel therapeutic strategies to prevent inflammation and improve T cell function in obese patients.
