Several components of the signaling pathways associated with the Fas receptor are involved in insulin secretion (14, 15) and physiological adjustment of β-cell mass. For example, the antiapoptotic factor FADD-like interleukin-1β-converting enzyme-inhibitory protein acting as a competitive caspase-8 antagonist promotes β-cell growth (16) under the inductive influence of interleukin-1β (IL-1β) (17). The Fas signaling pathway is also involved in regulation of insulin secretion (14, 15).

Physiological immune privilege uses FasL to defend organs from excessive inflammation that is often more harmful than pathogens, such as the anterior eye chamber and reproductive organs (10, 18). The pancreas is not one of the first line immune privileged tissues. However, both islet cells and vascular endothelium constitutively express FasL, while the Fas receptor is prevalently detected in resident macrophages (19, 20) and in inflamed islets (21, 22). The histological pattern of expression is suggestive of a defensive rim of FasL-expressing α- and β-cells in the islets of Langerhans (23). In fact, the frontier battleground between reactive T cells and tissues is islet vasculature (24), which constitutively expresses both Fas and FasL (25) and is therefore inherently insensitive to Fas-mediated apoptosis (26, 27). Protection of the islets by relative immune privilege represents a wider network of defense of the pancreas from incidental inflammation and immune attack (28) due to the extensive digestive capacity of pancreatic enzymes responsible for intestinal degradation of substrates, which might cause autolytic pancreatitis associated with severe morbidity and mortality.

Naïve islets express low levels of Fas (21, 22) and are intrinsically resistant to apoptosis triggered by this receptor (29, 30). Islets become gradually sensitive to apoptosis along the course of inflammation (31–33) due to increased Fas expression in β-cells (34, 35) and concomitant sensitization to Fas-mediated apoptosis (36, 37). Upregulated expression of the Fas receptor is one of the many features of the transcriptional profiles of inflamed islets (38, 39) caused by activation of the nuclear factor-κB (NFκB) pathways (40). Induced Fas transcription and modulation of expression is caused by a number of proinflammatory cytokines including IL-1α, IL-1β, IFNγ, nitric oxide (NO), and TNF-α that synergize with Fas as effector mechanisms of β-cell destruction (37, 41). Furthermore, both Fas expression induced by IL-1β (42) independent of NFκB activation (43, 44) and islet sensitization to apoptosis (45, 46) also evolve as direct consequences of hyperglycemia. The vast changes in transcriptomes and expression profiles of the inflamed islets may be viewed as an effort of the tissue to sustain insulin production and increase β-cell mass. However, cytokines secreted by the islets themselves paradoxally enhance immune activation and islet injury under inflammatory conditions (47–49).

There is extensive evidence emphasizing a pivotal role of the Fas/FasL interaction in destructive insulitis in T1D, including experiments performed in transgenes deficient in the receptor and/or the ligand. For example, homozygous transgenes of non-obese diabetic (NOD) mice deficient in the Fas receptor (lpr) are protected from spontaneous evolution of diabetes, and heterozygous NOD.lpr transgenes display severe mononuclear infiltration in the islets without hyperglycemia (50, 51). However, NOD.lpr with and without superposed SCID mutations that display reduced incidence of spontaneous diabetes are susceptible to islet injury inflicted by adoptive transfer of diabetogenic cells (52). Likewise, disease incidence is reduced in FasL-deficient transgenes (gld) crossed onto the NOD background (52, 53). It is logical and tempting to approach inflammatory insulitis by neutralization of the Fas/FasL interaction as one of the pivotal cytotoxic mechanisms used by diabetogenic effectors to attack β-cells (54–57), similar to the potential therapeutic benefit of TNF-α neutralization (58). However, it should be noted that FasL neutralization in the early postnatal period (53, 59) and in very early stages of inflammation slowed the pace but failed to prevent evolution of insulitis (60).

The insights into effective disease diversion by interruption of functional Fas/FasL signaling led to identification of a number of indirect immunogenic factors that modulate the course of inflammation in transgenic mice. The variable patterns of disease expression in lpr transgenes are explained by two mechanisms beyond relative insensitivity of Fas-deficient islets to apoptosis. First, slow pace of spontaneous inflammatory insulitis is attributed to reduced aggressiveness and slow proliferation of effector lymphocytes of the lpr transgenes (61). Second, T cells of lpr transgenes overexpress FasL, which inhibits the activity of endogenous and adoptively transferred diabetogenic cells (62). In variance, the pace of disease is slowed in gld transgenes by the activity of B lymphocytes that attenuate the course of inflammation by enhanced secretion of IL-10 (63). It is therefore evident that disruption of a pivotal immune homeostatic mechanism such as the Fas/FasL interaction has quite significant consequences that affect autoimmunity beyond direct participation as a cytotoxic mechanism of islet injury.

The difficulty in designation of an exact role of Fas-mediated apoptosis stands in the multiple, redundant, and interrelated mechanisms of β-cell death in T1D. The progressive involvement of Fas as a mediator of apoptosis along the course of inflammation has been challenged by a series of studies showing that this mechanism is neither obligatory nor essential in the process of destructive insulitis (64–68). Although Fas expression correlates with β-cell inflammation and unequivocally contributes to destructive insulitis, a causal relationship is rather complex because apoptosis also correlates with upregulation of granzyme and TNF-R1 (69–72). In addition to the canonical mechanisms of apoptosis, islet injury is inflicted by a number of cytotoxic cytokines such as IL-1β, IFNγ, and NO (73, 74). It is quite difficult to attribute distinct activities to these interrelated mechanisms in the process of inflammatory insulitis, because most cytokines as well as TNFα induce Fas expression (21, 22, 29, 75).

Each one of the canonical cytotoxic mechanisms, including Fas, TNF-R1, and perforin/granzyme, is dispensable in autoimmune β-cell destruction (68, 75–80), as well as islet allograft rejection (27, 81). Outstanding is the compensation of dysfunctional Fas/FasL interactions by other effector mechanisms of β-cell death (11, 35, 69, 82–84). Likewise, redundant activity of TGF-β, IL-1β, IFNγ, and NO is a common characteristic, as each individual cytotoxic mechanism is largely dispensable in β-cell lysis (36, 41, 47, 85).

Extending the mechanism of immune privilege, negative regulation of immune cells by TNF family receptor/ligand interactions has significant homeostatic impact on the intensity of inflammatory reactions. The common mechanism of tissue defense involves induction of apoptosis in autoreactive effectors sensitive to AICD at the level of pancreatic islets in situ (30, 62, 86). Physical elimination of diabetogenic cells has been attained by targeted expression of TNFα (87–90) and TGFβ (91, 92) under control of the insulin promoter, systemic administration of TNF-α (93–95), and overexpression of FasL protein in regulatory T cells (30, 96).

The analysis presented here suggests that inhibition of the Fas/FasL interaction has little potential efficacy in prevention of β-cell destruction by inflammatory insulitis, while targeted reinforcement of this mechanisms of immune homeostasis holds the potential to abrogate diabetic autoimmunity. Signaling through Fas receptor is one of many redundant and dispensable mechanisms of β-cell lysis by autoimmune attack; thus, neutralization provides transient symptomatic relief with little impact on alternative cytotoxic mechanisms (64–67). Implementation of FasL neutralization for treatment of T1D might even result in increased incidence of malignancies as seen with TNF-α inhibitors (97–99). On the contrary, the role of FasL along TNF-α and perforin/granzyme is much more significant and non-redundant in immune homeostasis than in induction of β-cell death (10, 61, 62, 88, 100). These homeostatic immune mechanisms counteract inflammation as mediators of effector cell death (27, 30, 86, 89–96) are mandatory to reinstitution of suppressor mechanisms (101) and are indispensable in termination of inflammatory reactions (4).