Apoptosis of CD4+ CD25(high) T cells in type 1 diabetes may be partially mediated by IL-2 deprivation.
BACKGROUND
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease targeting the insulin-producing pancreatic beta cells. Naturally occurring FOXP3(+)CD4(+)CD25(high) regulatory T cells (T(regs)) play an important role in dominant tolerance, suppressing autoreactive CD4(+) effector T cell activity. Previously, in both recent-onset T1D patients and beta cell antibody-positive at-risk individuals, we observed increased apoptosis and decreased function of polyclonal T(regs) in the periphery. Our objective here was to elucidate the genes and signaling pathways triggering apoptosis in T(regs) from T1D subjects.


RESULTS
Gene expression profiles of unstimulated T(regs) 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 T(regs) 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 T(regs) from T1D subjects partially mirrored the response of healthy T(regs) 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, T(regs) in T1D may be caught up in a relatively deficient cytokine milieu.


CONCLUSIONS
In summary, expression signatures in T(regs) 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 T(reg) function in subjects predisposed to T1D.
Jailwala
Parthav
P
The Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America.
Waukau
Jill
J
Glisic
Sanja
S
Jana
Srikanta
S
Ehlenbach
Sarah
S
Hessner
Martin
M
Alemzadeh
Ramin
R
Matsuyama
Shigemi
S
Laud
Purushottam
P
Wang
Xujing
X
Ghosh
Soumitra
S
D017209:Apoptosis / Q000235:genetics; D001499:Bayes Theorem; D015704:CD4 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
D015704:CD4 Antigens; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit