Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity

Abstract

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately two-fold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we demonstrate that engineered haplodeficiency of IL-2 gene expression not only reduces T cell IL-2 production by two-fold but also mimics the autoimmune dysregulatory effects of the naturally-occurring susceptibility alleles of IL-2. Reduced IL-2 production achieved by both genetic mechanisms correlates with fewer and less functional CD4+CD25+ regulatory T cells, which are critical for maintaining immune homeostasis.Multifactorial diseases with high population prevalence develop as a result of interactions between multiple genetic and environmental factors. Since the early 1990s, several loci have been mapped by genetic linkage and association analyses in humans and in rodent models of autoimmune disease, including type 1 diabetes (T1D). T1D is caused by the destruction of the insulin-producing pancreatic beta cells by various immune cell types, including CD8+ cytotoxic T-cells. In human T1D, four loci, in addition to the HLA region, have been identified: the genes encoding insulin, the negative immunoregulatory molecules CTLA-4 and LYP, and, most recently, the alpha chain of the interleukin-2 receptor (CD25) 1 . All of these common variants or haplotypes support the concept that autoimmunity is a part of normal physiology, and that the balance between immune responses to foreign antigens and

A cis-Acting Regulatory Variant in the IL2RA Locus

“…One obvious mechanism suggested is that lower IL2RA expression may decrease IL2 signaling, crucial for the suppression of autoimmunity by regulatory T cells, consistent with a similar effect of lower IL-2 production determined by the Idd3 locus in the NOD mouse (17). CD4 ϩ CD25 ϩ T cells, naturally generated in the thymus, is a population of regulatory T cells that plays an important role in maintaining immune homeostasis and inhibiting autoimmune disease by suppressing activated T cells (18).…”

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

“…This attenuated TCR/CD3 signaling could synergize with the 50% reduction in IL-2 abundance and correlate with the reduced function of regulatory T cells reported to be conferred by the NOD allele of the Idd3 locus (49). As recently discussed (50), such a scenario concurs with the quantal theory of immunity, stating that T cell responses depend on cells receiving a critical number of TCR-and IL-2R-mediated stimuli, which, in turn, may have consequences for the process of discrimination between self and nonself (51).…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…However, recent work suggest that differences between diabetes-prone NOD mice and other mice strains may reside in Treg function. Mechanisms, including age-related decline of transforming growth factor (TGF)-β production (Gregg et al 2004), interleukin (IL)-2 insufficiency (Yamanouchi et al 2007), resistance of effector T cells to regulation (D'Alise et al 2008), or an unusually reduced TCR diversity (Ferreira et al 2014), are often cited to explain these differences in animal models.…”