Apoptosis of CD4+CD25high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation

Abstract

BackgroundType 1 diabetes (T1D) is a T-cell mediated autoimmune disease targeting the insulin-producing pancreatic β cells. Naturally occurring FOXP3+CD4+CD25high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing autoreactive CD4+ effector T cell activity. Previously, in both recent-onset T1D patients and β cell antibody-positive at-risk individuals, we observed increased apoptosis and decreased function of polyclonal Tregs in the periphery. Our objective here was to elucidate the genes and signaling pathways triggering apoptosis in Tregs from T1D subjects.Principal FindingsGene expression profiles of unstimulated Tregs from recent-onset T1D (n = 12) and healthy control subjects (n = 15) were generated. Statistical analysis was performed using a Bayesian approach that is highly efficient in determining differentially expressed genes with low number of replicate samples in each of the two phenotypic groups. Microarray analysis showed that several cytokine/chemokine receptor genes, HLA genes, GIMAP family genes and cell adhesion genes were downregulated in Tregs from T1D subjects, relative to control subjects. Several downstream target genes of the AKT and p53 pathways were also upregulated in T1D subjects, relative to controls. Further, expression signatures and increased apoptosis in Tregs from T1D subjects partially mirrored the response of healthy Tregs under conditions of IL-2 deprivation. CD4+ effector T-cells from T1D subjects showed a marked reduction in IL-2 secretion. This could indicate that prior to and during the onset of disease, Tregs in T1D may be caught up in a relatively deficient cytokine milieu.ConclusionsIn summary, expression signatures in Tregs from T1D subjects reflect a cellular response that leads to increased sensitivity to apoptosis, partially due to cytokine deprivation. Further characterization of these signaling cascades should enable the detection of genes that can be targeted for restoring Treg function in subjects predisposed to T1D.

Restoring Regulatory T Cells in Type 1 Diabetes

“…When using the surface phenotype CD4 Tregs from T1D subjects have higher propensity to produce IFN [72]. In addition, Tregs in T1D subjects are prone to apoptosis, which is associated with a gene expression signature similar 9 to that of Tregs undergoing IL-2 deprivation [73][74][75], consistent with the reported defects in IL-2R signaling in T1D patients [57,76].…”

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

“…The role of GIMAPs in human diseases is underpinned by the observation that a single nucleotide polymorphism in GIMAP5 is associated with IA2 autoantibodies in type 1 diabetes (T1D) patients and systemic lupus erythematosus (16,17). The expression of almost the whole GIMAP family is turned down in regulatory T cells of patients suffering from T1D (18). Furthermore, GIMAPs belong to the most down-regulated proteins in anaplastic large cell lymphomas compared to the progenitor T cells (19).…”

Regin in Blood Immune Regulation in Type 1 Diabetes

“…Another study of Treg in T1D found neither in vitro functional defects nor changes in frequency of CD4 + CD25 hi Treg in T1D subjects [164]. The contrasting findings could be due to different approaches to discriminate [165], and instability of the Treg pool could potentially contribute to autoimmunity if antigen specific Treg are not maintained. The current consensus is that the frequency of Treg in T1D is not affected, but rather their function seems to be impaired.…”