IFN-γ Affects Homing of Diabetogenic T Cells

Abstract

IFN-γ is a cytokine with pleiotropic functions that participates in immune and autoimmune responses. The lack of IFN-γ is known to delay the development of autoimmune diabetes in nonobese diabetic (NOD) mice. Splenocytes from diabetic NOD and IFN-γ knockout (KO) NOD mice transfer diabetes into NOD recipients equally well. However, adoptive transfer of diabetogenic T cells from NOD mice into NOD.IFN-γ-KO or NOD mice lacking β-chain of IFN-γ receptor (NOD.IFN-γRβ-KO) appeared to be much less efficient. We found that IFN-γ influences the ability of diabetogenic cells to penetrate pancreatic islets. Tracing in vivo of insulin-specific CD8+ T cells has shown that homing of these cells to the islets of Langerhans was affected by the lack of IFN-γ. While adhesion of insulin-specific CD8+ cells to microvasculature was normal, the diapedesis was significantly impaired. This effect was reversible by treatment of the animals with rIFN-γ. Thus, IFN-γ may, among other effects, influence immune and autoimmune responses by supporting the homing of activated T cells.

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

“…Interferon-γ may be an important factor involved in the induction of MAdCAM-1 expression in islets of Langerhans [33]. Experimental diabetes models using different IFNγ-deficient mice have shown that this cytokine is crucial in controlling the homing of diabetogenic T cells into islets [34,35]. In the absence of IFNγ, diabetogenic T cells accumulate in the exocrine tissue or at the islet vascular isthmus, comparable to the histological results presented in this study.…”

Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

“…IFN-γ plays an important role in establishing insulitis and maintaining diabetogenic activity of the islet infiltrate by in part regulating the production of recruitment/retention cues, such as adhesion molecules and chemokines by islet resident cells (50). Indeed, suppression of IFN-γ by YTS resulted in decreased expression of chemokines, including IFN-γ-regulated CXCL9 and 10 ( Figure 2F).…”

CD4 T cell differentiation in type 1 diabetes

“…There are a number of ways in which IFN-g could be envisaged to contribute to the disease process including by up-regulating expression of major histocompatibility complex (MHC) classes I and II, facilitating macrophage activation, and increasing leucocyte extravasation by inducing adhesion molecules and chemokines (reviewed in [15]). Indeed IFN-g has been implicated in promoting the homing of diabetogenic T cells to the pancreatic islets in the NOD mouse [16]. There is also a substantial literature directly implicating the IFN-g signalling pathway in beta cell death, the critical destructive event at the heart of autoimmune diabetes.…”

“…IFN-g drives a persistent signal in pancreatic beta cells that can be inhibited by overexpression of suppressor of cytokine signalling-1 (SOCS1) [17], and islet expression of SOCS1 was found to be protective in the rat insulin promoter-lymphocytic choriomeningitis virus (RIP-LCMV) mouse model of diabetes [18]. Both IFN-g -/- [16] and IFN-gR -/- [19] islets are killed less effectively in vitro by CD8 T cells [16] and cytokines [19]. It is particularly striking that beta cells lacking IFN-gR show reduced sensitivity not just to IFN-g induced death, but also to TNF-a-and IL-1b-induced death [19], highlighting the capacity of IFN-g to sensitize beta cells to multiple potential death triggers.…”