Cross-talk between activated immune cells exacerbates inflammation in type 2 diabetes
MetadataShow full item record
Lymphocytes and myeloid cells (monocytes/macrophages) play important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role immune cells play in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies over-nutrition, and thus are critical players in metabolic homeostasis and T2D. However, multiple studies indicate important proinflammatory changes in B cells and T cells in mouse models of T2D, yet their specific contributions have yet to be fully elucidated in human T2D. The studies herein identify novel pro-inflammatory changes in the B cell compartment of T2D patients, showing that B cells from diabetic patients contribute to the inflammatory milieu through TLR mediated IL-8 production, along with a reduction in IL-10 production. These studies further demonstrate that T cells from T2D patients contribute to the inflammatory milieu by secreting elevated levels of the potent pro-inflammatory cytokine IL-17, following requisite cell contact with monocytes. Previous studies had established that interactions between monocytes, T cells and B cells are essential for proper immune responses and changes in disease states can alter these interactions. The data presented here show an important role for cell-cell cross-talk between B cells, T cells and monocytes, in which monocyte-T cell interactions lead to moderate levels of IL-17 from both T2D patients and ND controls but the interaction between B cells and T cells increases IL-17 production only in T cells from T2D patients. Taken together, these studies indicate that, in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets and cross-talk among them play important roles in T2D disease pathogenesis. These conclusions are integrated into a model consistent with the general emerging view that alterations in lymphocyte function in obesity and T2D are an integral part of a feed-forward pro-inflammatory loop involving additional cell types such as adipocytes, which respond to pro-inflammatory cytokines produced by immune cells.
Thesis (Ph.D.)--Boston University