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Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes.

Ferraro A, Socci C, Stabilini A, Valle A, Monti P, Piemonti L, Nano R, Olek S, Maffi P, Scavini M, Secchi A, Staudacher C, Bonifacio E, Battaglia M - Diabetes (2011)

Bottom Line: We found upregulation of Th17 immunity and functional defects in CD4(+)CD25(bright) Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood.The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.

ABSTRACT

Objective: Autoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect. Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease.

Research design and methods: We phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects.

Results: We found upregulation of Th17 immunity and functional defects in CD4(+)CD25(bright) Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood. In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients. The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.

Conclusions: These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

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Related in: MedlinePlus

Immune status in the PLN and PB of diabetic patients. A: Treg/Th17 and Treg/Th1 cell ratio was determined by TSRD and chemokine-receptor expression in the indicated donors and samples. HC, healthy control subjects; ND, nondiabetic donors; T1D, type 1 diabetic patients. Each symbol identifies a patient (as described in Supplementary Table 1), and the Mann-Whitney–Wilcoxon test was used for group comparisons. B: Correlation between the frequency of IL-17-producing CD4+ T cells and the suppressive function of CD25bright T cells isolated from PLN of diabetic (light symbols) and nondiabetic (bold filled circles) subjects. The linear regression analysis was used to compare the two measurements.
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Figure 6: Immune status in the PLN and PB of diabetic patients. A: Treg/Th17 and Treg/Th1 cell ratio was determined by TSRD and chemokine-receptor expression in the indicated donors and samples. HC, healthy control subjects; ND, nondiabetic donors; T1D, type 1 diabetic patients. Each symbol identifies a patient (as described in Supplementary Table 1), and the Mann-Whitney–Wilcoxon test was used for group comparisons. B: Correlation between the frequency of IL-17-producing CD4+ T cells and the suppressive function of CD25bright T cells isolated from PLN of diabetic (light symbols) and nondiabetic (bold filled circles) subjects. The linear regression analysis was used to compare the two measurements.

Mentions: The Treg/Th17 cell balance could be key in controlling autoimmune diseases, type 1 diabetes included (38,39). Our data show that the PLNs of diabetic patients are enriched in Th17 cells while having similar numbers of bona fide epigenetically imprinted Tregs. To determine whether there is a compensatory mechanism by which Tregs expand in those patients in which Th17 cells are more frequent, we measured the Treg/Th17 cell ratio as determined by TSRD analysis and chemokine receptor expression, respectively. The Treg/Th17 cell ratio was about four to five times lower in the PLNs of diabetic patients compared with nondiabetic donors, but was not different in the PB. Such an inverse correlation was not found between Tregs and Th1 cells (Fig. 6A). Thus, the immune balance is shifted toward a Th17-proinflammatory environment only in the target organ of long-lasting diabetic patients and not in their PB.


Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes.

Ferraro A, Socci C, Stabilini A, Valle A, Monti P, Piemonti L, Nano R, Olek S, Maffi P, Scavini M, Secchi A, Staudacher C, Bonifacio E, Battaglia M - Diabetes (2011)

Immune status in the PLN and PB of diabetic patients. A: Treg/Th17 and Treg/Th1 cell ratio was determined by TSRD and chemokine-receptor expression in the indicated donors and samples. HC, healthy control subjects; ND, nondiabetic donors; T1D, type 1 diabetic patients. Each symbol identifies a patient (as described in Supplementary Table 1), and the Mann-Whitney–Wilcoxon test was used for group comparisons. B: Correlation between the frequency of IL-17-producing CD4+ T cells and the suppressive function of CD25bright T cells isolated from PLN of diabetic (light symbols) and nondiabetic (bold filled circles) subjects. The linear regression analysis was used to compare the two measurements.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198077&req=5

Figure 6: Immune status in the PLN and PB of diabetic patients. A: Treg/Th17 and Treg/Th1 cell ratio was determined by TSRD and chemokine-receptor expression in the indicated donors and samples. HC, healthy control subjects; ND, nondiabetic donors; T1D, type 1 diabetic patients. Each symbol identifies a patient (as described in Supplementary Table 1), and the Mann-Whitney–Wilcoxon test was used for group comparisons. B: Correlation between the frequency of IL-17-producing CD4+ T cells and the suppressive function of CD25bright T cells isolated from PLN of diabetic (light symbols) and nondiabetic (bold filled circles) subjects. The linear regression analysis was used to compare the two measurements.
Mentions: The Treg/Th17 cell balance could be key in controlling autoimmune diseases, type 1 diabetes included (38,39). Our data show that the PLNs of diabetic patients are enriched in Th17 cells while having similar numbers of bona fide epigenetically imprinted Tregs. To determine whether there is a compensatory mechanism by which Tregs expand in those patients in which Th17 cells are more frequent, we measured the Treg/Th17 cell ratio as determined by TSRD analysis and chemokine receptor expression, respectively. The Treg/Th17 cell ratio was about four to five times lower in the PLNs of diabetic patients compared with nondiabetic donors, but was not different in the PB. Such an inverse correlation was not found between Tregs and Th1 cells (Fig. 6A). Thus, the immune balance is shifted toward a Th17-proinflammatory environment only in the target organ of long-lasting diabetic patients and not in their PB.

Bottom Line: We found upregulation of Th17 immunity and functional defects in CD4(+)CD25(bright) Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood.The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.

ABSTRACT

Objective: Autoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect. Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease.

Research design and methods: We phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects.

Results: We found upregulation of Th17 immunity and functional defects in CD4(+)CD25(bright) Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood. In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients. The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.

Conclusions: These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

Show MeSH
Related in: MedlinePlus