Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

Abstract

The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…The most significant difference in the contrasting effects of Cy and IL2-cas on the immune system of NOD mice was the expression of FOXP3, considered to be the characteristic marker of Treg [16,34] that best defines a suppressive phenotype in the pancreas [18]. Administration of Cy to NOD and wild-type mice resulted in a sharp decline in FOXP3 + T cells, corroborating prior reports [4,5].…”

“…Reactive changes in CD25, CD62L and FOXP3 as phenotypic markers of putative Treg have been previously observed with immunomodulatory agents such as Cy, anti-IL-2, anti-CD25 and anti-CD3, and have been generally associated with positive outcome of immunomodulation in NOD mice [4,5,16,28]. A similar reactive increase in FOXP3 expression has recently been associated with beneficial effects of Treg activation achieved by several immunomodulatory modalities, including IL-2/IL-2 antibody complexes, anti-thymocyte globulin, complete Freund's adjuvant, vasoactive intestinal peptide and rapamycin [18,[40][41][42][43][44]. Considering the very different mechanisms of action of these agents, it can be proposed that dominance of CD25 − FOXP3 + T cells is mediated by superior survival and faster expansion.…”

“…Likewise, administration of multiple low-doses of a complex composed of IL-2 and anti-IL-2 antibody prevented insulitis in NOD mice by increasing the numbers of Treg in the pancreas [17]. These data depict a scenario where IL-2 deficiency within the islets is detrimental to the function of Treg and favours evolution of the autoimmune reaction, whereas administration of large doses of IL-2 precipitates the disease through expansion of effector cells [18].…”

“…First, direct introduction of toxic moieties through the IL-2/ IL-2 receptor complex overcomes the relative resistance of NOD lymphocytes to apoptosis (as compared with wildtype mice) [49,50], and the decreased susceptibility of diabetogenic cells to Treg-mediated inhibition [33,51,52]. Inasmuch as B cell lymphoma protein 2 (BCL-2) is associated with the survival of islet-infiltrating T cells [18], IL2-cas was found to reduce the BCL-2/apoptosis regulator BAX ratio in a model of toxic colitis [25], suggesting that the fusion protein sensitises pathogenic lymphocytes to apoptosis. Thus, fusion proteins comprising IL-2 and toxic moieties are of therapeutic value irrespective of concomitant depletion of CD25 + Treg in NOD mice and models of inflammatory colitis [22,23], which are associated with aberrant sensitivity of the pathogenic cells to apoptosis.…”

“…Increased fractional expression of FOXP3 in NOD mice after targeted depletion of CD25 + T cells may be caused either by relative insensitivity of CD4 + FOXP3 + T cells to apoptosis, faster proliferation rates or induced expression of FOXP3 [4,5,18,24]. To dissociate between these possibilities, we next determined whether IL2-cas induces FOXP3 expression and/or stimulates proliferation of various CD4 + T cell subsets in vitro.…”