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

Abstract

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.