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Receptor/ligand interactions of the tumor necrosis factor (TNF) superfamily are associated with versatile apoptotic and regulatory signaling pathways in parenchymal tissues and the immunohematopoietic system. Apoptotic signaling mediated by Fas and TNF receptor-1 (TNF-R1) is one of the major cytotoxic mechanisms used by immune cells to kill endogenous cells and exogenous pathogens. In this capacity, these ubiquitous effector mechanisms of cell death, along with perforin/granzyme, are direct mediators of β-cell injury that is inflicted in autoimmune insulitis in type 1 diabetes (T1D). At the same time, the TNF family receptor/ligand interactions are prime constituents of immune homeostasis that enforce negative regulation of sensitized immunocytes (1–3). All immune cells upregulate TNF family receptors upon activation and are therefore submitted to negative regulation by apoptosis within the process of activation-induced cell death (AICD), which is also essential to termination of inflammation (4).  Tumor necrosis factor family receptor/ligand interactions participate as universal cytotoxic mechanisms in physiological turnover of cells, removal of dysfunctional cellular elements, and clearance of debris following injury of parenchymal tissues. As ubiquitous injury factors, the TNF family ligands concomitantly activate precursors and synergize with other growth factors to induce generation of renewed functional parenchymal cells to replace the injured tissue. For example, the Fas receptor and the cognate Fas-ligand (FasL) are constitutively expressed and transduce trophic regulatory signals in tissues such as glia, neurons, hepatocytes, and endothelium (5–7). Likewise, trophic signals are transduced by TNF superfamily receptors in hematopoietic stem and progenitor cells, which synergize with other growth factors to foster hematopoiesis under stress conditions (8). Therefore, common injury factors such as TNFα and interferons (IFN) couple hematopoietic activity to inflammation and injury in order to fuel immune reactions and support initial resolution of injury (9).  The Fas/FasL interaction is a common effector mechanism of β-cell apoptosis and islet injury under inflammatory conditions, and physiological modulation of immune homeostasis, including control of aberrant autoimmune reactions. In the absence of specific characteristics of the toxic and anti-inflammatory pathways, it is questioned whether neutralization or reinforcement of the Fas/FasL interaction is of therapeutic value in autoimmune disorders. We examine a wide array of evidence arguing in favor of and against therapeutic neutralization of Fas and/or FasL and conversely, consider the feasibility of implementation of this molecular interaction as approaches to abrogate autoimmune diabetes. Despite focus on a particular signaling pathway, the Fas/FasL interaction, in a particular autoimmune disorder, T1D, the debate is rather relevant to multiple receptor/ligand interactions of the TNF superfamily and to the entire range of inflammatory and autoimmune disorders.

frontiers in immunology

Fas/Fas-Ligand Interaction As a Mechanism of Immune Homeostasis and β-Cell Cytotoxicity: Enforcement Rather Than Neutralization for Treatment of Type 1 Diabetes