Metabolic Mechanisms of Nutritionally Regulated Hormone Signaling on T Helper Cell Function

<p>Nutritionally regulated hormones communicate nutritional status to cells and tissues throughout the body. In the case of overnutrition or obesity, levels of leptin, insulin, and insulin like growth factor 1 (IGF-1) are increased, whereas they are decreased in the setting of undernutrition. Either undernutrition or overnutrition results in a dysregulated immune response that contributes to increased susceptibility to infection. Immune cells, especially T cells, are responsive to nutritional hormone signals. Leptin has been shown to promote inflammatory CD4+ T cell differentiation, while insulin and IGF-1 have been shown to promote increased metabolism and function of various CD4+ T cell subsets. Here, we set out to understand how nutritionally regulated hormone signaling to T cells impacts T cell metabolism and function and thereby influences immunity. In Chapter 2, we investigated the requirement for leptin receptor signaling on T cells in driving obesity-associated inflammation and glucose intolerance. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell differentiation and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context. Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined. In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Thus, T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity. In Chapter 3, we investigated the impact of insulin and IGF-1 signaling on CD4+ T cell metabolism and function. Insulin receptor (IR) and IGF-1 receptor (IGF-1R) have signaling pathways closely related to the leptin receptor signaling pathways, and are known to regulate metabolism. Using extracellular flux analysis, we determined that both insulin and IGF-1 increase glycolytic and oxidative metabolism of CD4+ T cells, but insulin has a more potent effect. However, IGF-1 acts specifically on Th17 cells to increase their IL-17 production and metabolism. Furthermore, IGF-1 treatment decreases mitochondrial membrane potential and mitochondrial ROS (mROS) production in Th17 cells, presumably to protect the cells from oxidative stress. Interestingly, both IR and IGF-1R appear to be required for this effect. This could indicate that the hybrid IR/IGF-1R is required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production. Finally, we determined that the decrease in mitochondrial membrane potential and mROS caused by IGF-1 treatment is mediated by uncoupling protein 2 (UCP2) activity, and that the effects of IGF-1 treatment can be reversed by UCP2 inhibition. Altogether, these studies implicate nutritionally regulated hormones in promoting CD4+ T cell metabolism and function both in health and disease. </p>

Author dc:creator

• McConnell, Kaitlin Kiernan

Advisor dc:contributor.advisor

• MacIver, Nancie J

• Immunology

Handle dc:identifier.uri

https://hdl.handle.net/10161/29099

OAI identifier oai:identifier

oai:dukespace.lib.duke.edu:10161/29099