Apoptosis of CD4+CD25high T cells in type 1 diabetes may be partially mediated by IL-2 deprivation

Parthav Jailwala, Jill Waukau, Sanja Glisic, Srikanta Jana, Sarah Ehlenbach, Martin Hessner, Ramin Alemzadeh, Shigemi Matsuyama, Purushottam Laud, Xujing Wang, Soumitra Ghosh

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Abstract

Background: Type 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 antibodypositive 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 Findings: Gene 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. Conclusions: In 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.

Original languageEnglish (US)
Article numbere6527
JournalPloS one
Volume4
Issue number8
DOIs
StatePublished - Aug 5 2009

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T-cells
insulin-dependent diabetes mellitus
Medical problems
interleukin-2
Type 1 Diabetes Mellitus
Interleukin-2
apoptosis
T-lymphocytes
Apoptosis
T-Lymphocytes
Genes
genes
Cytokines
cytokines
Cytokine Receptors
Bayes Theorem
risk groups
Chemokine Receptors
autoimmune diseases
Cell adhesion

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Jailwala, P., Waukau, J., Glisic, S., Jana, S., Ehlenbach, S., Hessner, M., ... Ghosh, S. (2009). Apoptosis of CD4+CD25high T cells in type 1 diabetes may be partially mediated by IL-2 deprivation. PloS one, 4(8), [e6527]. https://doi.org/10.1371/journal.pone.0006527

Apoptosis of CD4+CD25high T cells in type 1 diabetes may be partially mediated by IL-2 deprivation. / Jailwala, Parthav; Waukau, Jill; Glisic, Sanja; Jana, Srikanta; Ehlenbach, Sarah; Hessner, Martin; Alemzadeh, Ramin; Matsuyama, Shigemi; Laud, Purushottam; Wang, Xujing; Ghosh, Soumitra.

In: PloS one, Vol. 4, No. 8, e6527, 05.08.2009.

Research output: Contribution to journalArticle

Jailwala, P, Waukau, J, Glisic, S, Jana, S, Ehlenbach, S, Hessner, M, Alemzadeh, R, Matsuyama, S, Laud, P, Wang, X & Ghosh, S 2009, 'Apoptosis of CD4+CD25high T cells in type 1 diabetes may be partially mediated by IL-2 deprivation', PloS one, vol. 4, no. 8, e6527. https://doi.org/10.1371/journal.pone.0006527
Jailwala, Parthav ; Waukau, Jill ; Glisic, Sanja ; Jana, Srikanta ; Ehlenbach, Sarah ; Hessner, Martin ; Alemzadeh, Ramin ; Matsuyama, Shigemi ; Laud, Purushottam ; Wang, Xujing ; Ghosh, Soumitra. / Apoptosis of CD4+CD25high T cells in type 1 diabetes may be partially mediated by IL-2 deprivation. In: PloS one. 2009 ; Vol. 4, No. 8.
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AU - Jana, Srikanta

AU - Ehlenbach, Sarah

AU - Hessner, Martin

AU - Alemzadeh, Ramin

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