Leptin is a pleiotropic cytokine/hormone that has been shown to primarily play a critical role on food intake and energy expenditure but is also a participant in functions of the immune system, including that of antigen presenting cells (APCs). Of the three cell populations that constitute APCs, only one, dendritic cells (DC) have the ability to initiate naive T cell responses. Our goal is to assess the potential role of leptin on DC function particularly when signaling through the leptin receptor is compromised, such as in patients afflicted with obesity or Type II Diabetes. We have found, analyzing DC isolated and enriched from spleens of leptindeficient mice (Lepob), that some, but not all, of DC functions are affected when compared to splenic DC from control C57BI/6 mice. Preliminary data has shown that DC do express the long isoform of the leptin receptor and therefore can be responsive to leptin. Leptin-deficiency does not alter DC phenotype, DC activation by inflammatory stimuli, or processing of antigen;however, leptin-deficiency does affect DC ability to acquire antigen and to effectively activate T cells. We have also found that the addition of exogenous leptin to bone marrow-derived DC alters the morphology of the DC, promoting more and longer extensions and also enhances DC survival. We hypothesize that leptin signaling is reduced in DC from leptin-deficient mice due to a reduction in leptin receptor density and that normally, leptin enhances DC survival and dendrite formation thereby enhancing APC - T cell interactions leading to optimal T cell activation. We propose to address our hypothesis with three specific aims.
Aim 1 will determine the relative expression levels of the ong isoform of the leptin receptor on DC using standard Western blot analysis and Q-PCR.
Aim 2 will ascertain if leptin enhances DC survival when in co-culture with T cells by assessing the induction of DC apoptosis and will ascertain if leptin enhances DC - T cell conjugate formation by a number of microscopy techniques. Lastly, Aim 3 will evaluate the induction of signaling events in DC by leptin. More specifically, the induction of pro-survival signaling pathways will be evaluated biochemically and the induction of actin reorganization will be assessed via microscopy and biochemical assays. Considering the potential influence of eptin on DC maturation and function (as suggested by our preliminary data), resistance to leptin signaling tiat occurs in the obese and in type 2 diabetes may compromise DC function and thus T cell-mediated mmunity underscoring the clinical significance of understanding the role of leptin in immunity.
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