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Interleukin-1β produced in response to islet autoantigen presentation differentiates T-helper 17 cells at the expense of regulatory T-cells: Implications for the timing of tolerizing immunotherapy.

Bertin-Maghit S, Pang D, O'Sullivan B, Best S, Duggan E, Paul S, Thomas H, Kay TW, Harrison LC, Steptoe R, Thomas R - Diabetes (2010)

Bottom Line: IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred.IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells.RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia.

ABSTRACT

Objective: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB(lo) DCs in the prediabetic period.

Research design and methods: We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro.

Results: Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.

Conclusions: IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.

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Related in: MedlinePlus

IL-1β drives IL-6, TNF, IL-10, and IL-17, which are not subject to Treg suppression, as insulitis develops in NOD mice. Cytokines were assayed in supernatants from the T-cell proliferation assays (Fig. 3) from mice of the ages indicated using CBA kits and IL-17 ELISA. ○, cytokine production by CD4+CD25− T-cells in the absence of CD4+CD25+ Treg; ♦, cytokine production by CD4+CD25− T-cells in the presence of CD4+CD25+ Treg. A: Wild-type mice. B: NOD.IL-1R1−/− mice. Data represent mean ± SEM.
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Figure 4: IL-1β drives IL-6, TNF, IL-10, and IL-17, which are not subject to Treg suppression, as insulitis develops in NOD mice. Cytokines were assayed in supernatants from the T-cell proliferation assays (Fig. 3) from mice of the ages indicated using CBA kits and IL-17 ELISA. ○, cytokine production by CD4+CD25− T-cells in the absence of CD4+CD25+ Treg; ♦, cytokine production by CD4+CD25− T-cells in the presence of CD4+CD25+ Treg. A: Wild-type mice. B: NOD.IL-1R1−/− mice. Data represent mean ± SEM.

Mentions: Given the marked change in proinflammatory IL-1β secretion associated with altered Treg function during the insulitis phase in NOD mice, we extended our analysis to determine whether other proinflammatory cytokines were produced simultaneously and whether these could be suppressed by Treg cells. IL-6, tumor necrosis factor (TNF), IL-17, IFN-γ, and IL-10 were overexpressed at the same time as IL-1β (8–12 weeks). Treg did not suppress these cytokines when added to Teff (Fig. 4A). We did not observe similar increases in IL-6, IL-17, IFN-γ, or IL-10 when analyzing cells from NOD.IL-1R1−/− mice (Fig. 4B). TNF was overexpressed in NOD.IL-1R1−/− mice between weeks 5 and 10 but was suppressed by the addition of Treg. IL-23 was undetectable in these supernatants (data not shown).


Interleukin-1β produced in response to islet autoantigen presentation differentiates T-helper 17 cells at the expense of regulatory T-cells: Implications for the timing of tolerizing immunotherapy.

Bertin-Maghit S, Pang D, O'Sullivan B, Best S, Duggan E, Paul S, Thomas H, Kay TW, Harrison LC, Steptoe R, Thomas R - Diabetes (2010)

IL-1β drives IL-6, TNF, IL-10, and IL-17, which are not subject to Treg suppression, as insulitis develops in NOD mice. Cytokines were assayed in supernatants from the T-cell proliferation assays (Fig. 3) from mice of the ages indicated using CBA kits and IL-17 ELISA. ○, cytokine production by CD4+CD25− T-cells in the absence of CD4+CD25+ Treg; ♦, cytokine production by CD4+CD25− T-cells in the presence of CD4+CD25+ Treg. A: Wild-type mice. B: NOD.IL-1R1−/− mice. Data represent mean ± SEM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012178&req=5

Figure 4: IL-1β drives IL-6, TNF, IL-10, and IL-17, which are not subject to Treg suppression, as insulitis develops in NOD mice. Cytokines were assayed in supernatants from the T-cell proliferation assays (Fig. 3) from mice of the ages indicated using CBA kits and IL-17 ELISA. ○, cytokine production by CD4+CD25− T-cells in the absence of CD4+CD25+ Treg; ♦, cytokine production by CD4+CD25− T-cells in the presence of CD4+CD25+ Treg. A: Wild-type mice. B: NOD.IL-1R1−/− mice. Data represent mean ± SEM.
Mentions: Given the marked change in proinflammatory IL-1β secretion associated with altered Treg function during the insulitis phase in NOD mice, we extended our analysis to determine whether other proinflammatory cytokines were produced simultaneously and whether these could be suppressed by Treg cells. IL-6, tumor necrosis factor (TNF), IL-17, IFN-γ, and IL-10 were overexpressed at the same time as IL-1β (8–12 weeks). Treg did not suppress these cytokines when added to Teff (Fig. 4A). We did not observe similar increases in IL-6, IL-17, IFN-γ, or IL-10 when analyzing cells from NOD.IL-1R1−/− mice (Fig. 4B). TNF was overexpressed in NOD.IL-1R1−/− mice between weeks 5 and 10 but was suppressed by the addition of Treg. IL-23 was undetectable in these supernatants (data not shown).

Bottom Line: IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred.IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells.RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia.

ABSTRACT

Objective: The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-κB inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1β production and the response to RelB(lo) DCs in the prediabetic period.

Research design and methods: We injected RelB(lo) DCs subcutaneously into 4- or 14-week-old NOD mice and tracked the incidence of diabetes and effect on Treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of T effectors to Treg in vitro.

Results: Tolerizing RelB(lo) DCs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. IL-1β production by NOD splenocytes and mRNA expression by islets increased from 6 to 16 weeks of age when major histocompatibility complex (MHC)-restricted islet antigen presentation to autoreactive T-cells occurred. IL-1 reduced the capacity of Treg cells to suppress effector cells and promoted their conversion to Th17 cells. RelB(lo) DCs exacerbated the IL-1-dependent decline in Treg function and promoted Th17 conversion.

Conclusions: IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 at the expense of Treg. Tolerizing DC therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the IL-1β/IL-17 checkpoint signals the need for other strategies.

Show MeSH
Related in: MedlinePlus