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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

Enhanced Treg suppressive capacity in response to anti–IL-17. CD4+CD25+ and CD4+CD25− T-cells purified from spleens of wild-type mice administered anti–IL-17 mAb intraperitoneally on alternate days for 10 days 4 weeks prior at age 6 weeks were incubated alone or in a 1:1 ratio with DCs and anti-CD3. Proliferation was assessed by incorporation of [3H] thymidine and means ± SE; percent suppression was calculated. Three mice were pooled in each of two separate experiments. *P < 0.05 (t test).
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Figure 8: Enhanced Treg suppressive capacity in response to anti–IL-17. CD4+CD25+ and CD4+CD25− T-cells purified from spleens of wild-type mice administered anti–IL-17 mAb intraperitoneally on alternate days for 10 days 4 weeks prior at age 6 weeks were incubated alone or in a 1:1 ratio with DCs and anti-CD3. Proliferation was assessed by incorporation of [3H] thymidine and means ± SE; percent suppression was calculated. Three mice were pooled in each of two separate experiments. *P < 0.05 (t test).

Mentions: Although IL-1 impairs the suppressive function of Treg (Fig. 4) (17), a recent publication (49) showed that inhibition of IL-17 for 10 days in 10-week NOD mice was sufficient to impair progression to diabetes, associated with increased Treg infiltration of islets. When we treated 6-week NOD with anti–IL-17, Teff were suppressed by splenic Treg significantly better than those of untreated mice (Fig. 8). The data support the conclusion that in addition to the broad impact of IL-1, IL-17 itself impacts suppression by FoxP3+ Treg.


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)

Enhanced Treg suppressive capacity in response to anti–IL-17. CD4+CD25+ and CD4+CD25− T-cells purified from spleens of wild-type mice administered anti–IL-17 mAb intraperitoneally on alternate days for 10 days 4 weeks prior at age 6 weeks were incubated alone or in a 1:1 ratio with DCs and anti-CD3. Proliferation was assessed by incorporation of [3H] thymidine and means ± SE; percent suppression was calculated. Three mice were pooled in each of two separate experiments. *P < 0.05 (t test).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 8: Enhanced Treg suppressive capacity in response to anti–IL-17. CD4+CD25+ and CD4+CD25− T-cells purified from spleens of wild-type mice administered anti–IL-17 mAb intraperitoneally on alternate days for 10 days 4 weeks prior at age 6 weeks were incubated alone or in a 1:1 ratio with DCs and anti-CD3. Proliferation was assessed by incorporation of [3H] thymidine and means ± SE; percent suppression was calculated. Three mice were pooled in each of two separate experiments. *P < 0.05 (t test).
Mentions: Although IL-1 impairs the suppressive function of Treg (Fig. 4) (17), a recent publication (49) showed that inhibition of IL-17 for 10 days in 10-week NOD mice was sufficient to impair progression to diabetes, associated with increased Treg infiltration of islets. When we treated 6-week NOD with anti–IL-17, Teff were suppressed by splenic Treg significantly better than those of untreated mice (Fig. 8). The data support the conclusion that in addition to the broad impact of IL-1, IL-17 itself impacts suppression by FoxP3+ Treg.

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