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Central Role for Interleukin-2 in Type 1 Diabetes

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Central Role for Interleukin-2 in Type 1 Diabetes PERSPECTIVES IN DIABETES Central Role for Interleukin-2 in Type 1 Diabetes Maigan A. Hulme, Clive H. Wasserfall, Mark A. Atkinson, and Todd M. Brusko Type 1 diabetes presents clinically with overt hyperglycemia (3). Despite this critical requirement, Tregs do not produce resulting from progressive immune-mediated destruction of pan- their own IL-2 and are dependent on Tconv or dendritic creatic b-cells and associated metabolic dysfunction. Combined cells (DCs) for signals needed to maintain viability and genetic and immunological studies now highlight deficiencies in function. Therefore, a reduction in IL-2 signaling in type 1 both the interleukin-2 (IL-2) receptor and its downstream signal- diabetes may contribute to Treg decline and the emergence ing pathway as a central defect in the pathogenesis of type 1 of effector phenotypes. diabetes. Prior intervention studies in animal models indicate that Receptor clustering and signal thresholds. The IL-2 augmenting IL-2 signaling can prevent and reverse disease, with receptor is often modeled as a stand-alone structure con- protection conferred primarily by restoration of regulatory T-cell sisting of the individual a/b/gc subunits complexed with (Treg) function. In this article, we will focus on studies of type 1 A diabetes noting deficient IL-2 signaling and build what we believe IL-2 (Fig. 2 ). This schematic conveys the notion that IL-2 forms the molecular framework for their contribution to the dis- receptors are diffusely distributed across the cell surface. ease. This activity results in the identification of a series of poten- In fact, high-resolution microscopy studies suggest clus- tially novel therapeutic targets that could restore proper immune tering of receptors and signaling complexes adjacent to regulation in type 1 diabetes by augmenting the IL-2 pathway. immunological synapses (4). Furthermore, a careful anal- Diabetes 61:14–22, 2012 ysis of the X-ray crystallographic structure of the IL-2 tetrameric complex suggests that CD25/IL-2Rb may inter- act with the gc chain on a neighboring receptor, allowing for assembly of a cell surface network of receptor com- INTERLEUKIN-2 AND THE INTERLEUKIN-2 RECEPTOR plexes and increased responsiveness to IL-2 (5). This theory Physiological role and function. Understanding the role is supported by the observation of an extensive interaction of interleukin (IL)-2 in the etiology of type 1 diabetes between gc and IL-2Ra in the crystal structure, featuring requires knowledge of the regulation of—as well as the high shape complementarity as well as hydrogen bonding structural and functional consequences of—IL-2 binding to (Fig. 2B and C)(5). its cognate receptor (IL-2R). IL-2 can be used by cells Competition for gc dictates cellular activity: a role expressing either the intermediate-affinity (Kd = 1029 M) for membrane CD25. gc serves as a signaling compo- receptor dimer of IL-2Rb (CD122) and the common g chain nent in six distinct cytokine receptor assemblies, namely, (gc; CD132), or the high-affinity (Kd = 10211 M) trimeric the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors (6). Addi- IL-2R comprising IL-2Ra (CD25), IL-2Rb,andgc. The tionally, IL-2 and IL-15 both use IL-2Rb to propagate down- intermediate-affinity IL-2R is more broadly expressed on stream signaling. Cellular response to these cytokines is T cells, natural killer (NK) cells, and monocytes, whereas surprisingly variable despite this structural commonality. the high-affinity IL-2R is only constitutively expressed on This is due, in part, to differential association of adaptor regulatory T-cells (Tregs) (1). A simplified schematic of IL-2 proteins and downstream STATs with the unique receptor signaling in both Tregs and conventional T cells (Tconv), or subunits (Fig. 3) (6). There are, however, some functional differentiated (i.e., Th1, Th17) effector T cells (Teffs) can be redundancies (Fig. 3). formed (Fig. 1). IL-2 binding initiates signal transduction Competition among receptor subunits to use gc depends following cross-phosphorylation of tyrosine residues in on their expression level and the local cytokine environ- Janus-activated kinases (JAKs), leading to downstream ment. Experiments using fluorescence resonance energy phosphatidylinositol 3-kinase/Akt, mitogen-activated protein transfer and confocal microscopy have shown that CD25 and kinase/extracellular signal–related kinase, and signal trans- IL-15Ra are expressed within the same membrane micro- ducer and activator of transcription (STAT5) activation. domains (7). It has been theorized that multiple unique re- Functional impact of IL-2 signaling. Downstream cel- ceptor subunits are expressed in close proximity to gc, with lular response to IL-2 depends not only upon surface ex- rapid rearrangement to assemble the relevant receptor in pression of the receptor but also upon local cytokine response to cytokine presence (8). Extending these obser- concentration, target cell population, and modification of vations, the formation of a signaling zipper (Fig. 2C)could the various response elements in this complex pleiotropic prevent the association of gc with other cytokine receptor signaling pathway. For Tconv cells, high concentrations of subunits, effectively sequestering it for CD25 and IL-2 sig- IL-2 can cause activation-induced cell death (AICD), whereas naling machinery. Conversely, proteolytic shedding of a moderate to low concentrations of IL-2 induce effector or soluble form of CD25 from the cell surface may prevent this memory phenotypes, respectively (2). IL-2 signaling is crit- signaling complex formation and alter downstream IL-2 ical for the development, maintenance, and function of Tregs response (9). The effect of CD25 loss likely differs by cell type; for example, Tregs may exhibit reduced function, whereas activated T cells might slow their progress toward From the Department of Pathology, University of Florida, Gainesville, Florida. Corresponding author: Todd M. Brusko, [email protected]fl.edu. AICD. DOI: 10.2337/db11-1213 IL-2 signaling in non–T cells. Much of what is known Ó 2012 by the American Diabetes Association. Readers may use this article as about the IL-2R and its downstream activity has been de- long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by termined in T cells, given its unique role in adaptive T cell -nc-nd/3.0/ for details. responses. However, functional IL-2 receptors are expressed 14 DIABETES, VOL. 61, JANUARY 2012 diabetes.diabetesjournals.org M.A. HULME AND ASSOCIATES FIG. 1. A simplified schematic of IL-2 receptor signaling. In this diagram, and throughout this review, CD25 is shown in red, IL-2 in orange, IL-2Rb in blue, and gc in green. Briefly, JAK1 and JAK3 are phosphorylated by IL-2Rb and gc, and propagate downstream signaling through multiple pathways, which are uniquely regulated in Treg cells. Elements that are more active in Treg than in Teff or Tconv cells are shown in green (i.e., STAT5 and PTEN), while those that are more active in Teff or Tconv are shown in blue (i.e., phosphatidylinositol 3-kinase [PI3K]/Akt and mitogen- activated protein kinase [MEK]/extracellular signal–related kinase [Erk]). Proteins that are known to have genetic polymorphisms associated with type 1 diabetes risk are highlighted in red underlined text. on activated B cells, DCs, NK cells, and eosinophils (10– of these cell subsets would have on the disease process in 12). Information about the role of IL-2 signaling in non–T type 1 diabetes. cells is limited; yet existing data suggests a stimulatory role. Indeed, it has been shown that CD25+ B cells have increased costimulatory and migratory capacity (10). NK GENETIC DEFECTS IN THE IL-2 SIGNALING PATHWAY cells display enhanced activity upon CD25 expression Linking genes with function in mice and humans. (11), and eosinophil degranulation appears to be triggered Studies in the nonobese diabetic (NOD) mouse model and by IL-2 (12). The previous data provide clear evidence that in humans with type 1 diabetes have identified multiple high-affinity IL-2 signaling in non–T cells is rare, but may genes in the IL-2 signaling pathway that are associated with nonetheless impact a variety of immune cell subsets. What disease susceptibility (13) (Fig. 1). The clearest evidence de- remains unclear is how these cells might be affected by lineating a role for IL-2 in maintaining immune tolerance therapeutic doses of IL-2 and what, if any, impact activation derives from data generated in animal models. diabetes.diabetesjournals.org DIABETES, VOL. 61, JANUARY 2012 15 INTERLEUKIN-2 AND TYPE 1 DIABETES FIG. 2. High-affinity IL-2 receptor structure and interreceptor association. A: Crystal structure of the quaternary IL-2 receptor structure, depicting CD25 (red), IL-2Rb (blue) and gc(green) in interaction with IL-2 (orange). B: The enlarged panel highlights the area of interaction between gc and CD25 on a neighboring crystal unit. High complementarity and hydrogen bonding are features of this interaction. C: Depiction of the IL-2 signaling “zipper,” a repeating unit of high-affinity IL-2 receptors present in the solved crystal structure. The extensive complementarity of CD25 and gc interface in this structure suggests a physiologically relevant binding interaction. Mice that lack IL-2, CD25, IL-2Rb, or STAT5 all succumb penetrance and relatively common occurrence of these to lymphoproliferative disease due to a marked Treg re- variants in humans, the impact of having multiple gene duction. The administration of exogenous IL-2 or adoptive defects that affect IL-2 signaling has not been determined. transfer of wild-type T cells to deficient animals results in Intriguingly, the NOD mouse carries the majority of these the restoration of Tregs and peripheral immune regulation IL-2 signaling deficiencies, while in humans it is unknown if (1).
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