Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells

Abstract

Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset.

Keywords: NK cells; Type 1 Diabetes; autoimmune diseases.

Figure 1

The mechanism of action of NK cells depends on the fine balance between activating and inhibitory signals. The binding of ligands, present on the cell surface and encoded by pathogens or by the host, with activating NKRs leads to NK cells activation. More specifically, NK cells express inhibitory receptors specific for MHC (Major Histocompatibility Complex class I (MHC I)) molecules on target cells. Because of direct ligand interaction, these inhibitory receptors prevent NK cell activation and killing. NK cells also express activation receptors that recognize target cell ligands and can trigger perforin-dependent natural killing. In normal cells, the integration of both activating and inhibitory signals, due to the presence of MHC I molecules, contributes to the overall state of NK quiescence. Conversely, tumor, virus-infected and transplanted cells are characterized by an enhanced expression of activatory ligands, beside the lacking or downregulation of MHC I molecules on their surface. These cells are able to drive NKs toward their activation state thus promoting target cells lysis, through the exocytosis of granzymes- and perforin-containing granules.

Figure 2

Both genetic and environmental factors cause β cell apoptosis leading to β cell antigen release. Self-antigens induce APC activation. Activated APCs promote the activation of naïve T cells in the pancreatic lymph nodes. Autoreactive T cells infiltrate pancreatic islet and release pro-inflammatory factors promoting insulitis, amplifying the apoptotic process and reducing insulin production and secretion. NKs could be involved in one or multiple steps of the immune-mediated attack that lead to T1D, although their protective or promoting role in this process remains to be elucidated. NKs can affect the proliferation and generation of T and B autoreactive lymphocytes. Mature B cells differentiate in plasma cells (PCs) producing autoantibodies, which, in turn, further contribute to the tissue inflammatory process and destruction. NKs cells can also act as “memory like cells” expanding upon auto-antigenic exposure in response to viruses.