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DCIR2 + cDC2 DCs and Zbtb32 Restore CD4 + T-Cell Tolerance and Inhibit Diabetes

View Article: PubMed Central - PubMed

ABSTRACT

During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit tolerance in the steady state may not be effective. To determine which DC subsets induce tolerance in the context of chronic autoimmunity, we used chimeric antibodies specific for DC inhibitory receptor 2 (DCIR2) or DEC-205 to target self-antigen to CD11b+ (cDC2) DCs and CD8+ (cDC1) DCs, respectively, in autoimmune-prone nonobese diabetic (NOD) mice. Antigen presentation by DCIR2+ DCs but not DEC-205+ DCs elicited tolerogenic CD4+ T-cell responses in NOD mice. β-Cell antigen delivered to DCIR2+ DCs delayed diabetes induction and induced increased T-cell apoptosis without interferon-γ (IFN-γ) or sustained expansion of autoreactive CD4+ T cells. These divergent responses were preceded by differential gene expression in T cells early after in vivo stimulation. Zbtb32 was higher in T cells stimulated with DCIR2+ DCs, and overexpression of Zbtb32 in T cells inhibited diabetes development, T-cell expansion, and IFN-γ production. Therefore, we have identified DCIR2+ DCs as capable of inducing antigen-specific tolerance in the face of ongoing autoimmunity and have also identified Zbtb32 as a suppressive transcription factor that controls T cell–mediated autoimmunity.

No MeSH data available.


Related in: MedlinePlus

Stimulation of BDC2.5 T cells by DCIR2+ DCs delays diabetes development in NOD.scid mice. A: Percent of NOD.scid mice that are diabetes free after injection with CD4+CD25− BDC2.5 T cells and the indicated treatments. Statistical analysis was performed with log-rank test. P < 0.001 for αDEC-BDC vs. αDCIR2-BDC; P = 0.452 for PBS vs. αDEC-BDC. Summation of four experiments. n = 28 mice treated with PBS, n = 20 mice treated with αDEC-BDC, and n = 19 mice treated with αDCIR2-BDC. BDC2.5 T cells (5 × 104) were transferred to NOD.scid mice and treated with the indicated conditions. Graphs indicate the total BDC2.5 T-cell number (B) and the ratio of Foxp3+ BDC2.5 T cells (C) in NOD.scid mice on day 5. Average of three independent experiments ± SEM. Statistical analysis was performed with one-way ANOVA with Bonferroni posttest. *P < 0.05. LN, lymph nodes; NS, not significant.
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Figure 1: Stimulation of BDC2.5 T cells by DCIR2+ DCs delays diabetes development in NOD.scid mice. A: Percent of NOD.scid mice that are diabetes free after injection with CD4+CD25− BDC2.5 T cells and the indicated treatments. Statistical analysis was performed with log-rank test. P < 0.001 for αDEC-BDC vs. αDCIR2-BDC; P = 0.452 for PBS vs. αDEC-BDC. Summation of four experiments. n = 28 mice treated with PBS, n = 20 mice treated with αDEC-BDC, and n = 19 mice treated with αDCIR2-BDC. BDC2.5 T cells (5 × 104) were transferred to NOD.scid mice and treated with the indicated conditions. Graphs indicate the total BDC2.5 T-cell number (B) and the ratio of Foxp3+ BDC2.5 T cells (C) in NOD.scid mice on day 5. Average of three independent experiments ± SEM. Statistical analysis was performed with one-way ANOVA with Bonferroni posttest. *P < 0.05. LN, lymph nodes; NS, not significant.

Mentions: Differences between groups in diabetes experiments (Figs. 1A and 8E) were analyzed by the log-rank test. Analysis of all other data was done using an ANOVA analysis with Bonferroni posttests or an unpaired, two-tailed Student t test with 95% CI (GraphPad Prism, San Diego, CA). P values <0.05 were considered significant.


DCIR2 + cDC2 DCs and Zbtb32 Restore CD4 + T-Cell Tolerance and Inhibit Diabetes
Stimulation of BDC2.5 T cells by DCIR2+ DCs delays diabetes development in NOD.scid mice. A: Percent of NOD.scid mice that are diabetes free after injection with CD4+CD25− BDC2.5 T cells and the indicated treatments. Statistical analysis was performed with log-rank test. P < 0.001 for αDEC-BDC vs. αDCIR2-BDC; P = 0.452 for PBS vs. αDEC-BDC. Summation of four experiments. n = 28 mice treated with PBS, n = 20 mice treated with αDEC-BDC, and n = 19 mice treated with αDCIR2-BDC. BDC2.5 T cells (5 × 104) were transferred to NOD.scid mice and treated with the indicated conditions. Graphs indicate the total BDC2.5 T-cell number (B) and the ratio of Foxp3+ BDC2.5 T cells (C) in NOD.scid mice on day 5. Average of three independent experiments ± SEM. Statistical analysis was performed with one-way ANOVA with Bonferroni posttest. *P < 0.05. LN, lymph nodes; NS, not significant.
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Related In: Results  -  Collection

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Figure 1: Stimulation of BDC2.5 T cells by DCIR2+ DCs delays diabetes development in NOD.scid mice. A: Percent of NOD.scid mice that are diabetes free after injection with CD4+CD25− BDC2.5 T cells and the indicated treatments. Statistical analysis was performed with log-rank test. P < 0.001 for αDEC-BDC vs. αDCIR2-BDC; P = 0.452 for PBS vs. αDEC-BDC. Summation of four experiments. n = 28 mice treated with PBS, n = 20 mice treated with αDEC-BDC, and n = 19 mice treated with αDCIR2-BDC. BDC2.5 T cells (5 × 104) were transferred to NOD.scid mice and treated with the indicated conditions. Graphs indicate the total BDC2.5 T-cell number (B) and the ratio of Foxp3+ BDC2.5 T cells (C) in NOD.scid mice on day 5. Average of three independent experiments ± SEM. Statistical analysis was performed with one-way ANOVA with Bonferroni posttest. *P < 0.05. LN, lymph nodes; NS, not significant.
Mentions: Differences between groups in diabetes experiments (Figs. 1A and 8E) were analyzed by the log-rank test. Analysis of all other data was done using an ANOVA analysis with Bonferroni posttests or an unpaired, two-tailed Student t test with 95% CI (GraphPad Prism, San Diego, CA). P values <0.05 were considered significant.

View Article: PubMed Central - PubMed

ABSTRACT

During autoimmunity, the normal ability of dendritic cells (DCs) to induce T-cell tolerance is disrupted; therefore, autoimmune disease therapies based on cell types and molecular pathways that elicit tolerance in the steady state may not be effective. To determine which DC subsets induce tolerance in the context of chronic autoimmunity, we used chimeric antibodies specific for DC inhibitory receptor 2 (DCIR2) or DEC-205 to target self-antigen to CD11b+ (cDC2) DCs and CD8+ (cDC1) DCs, respectively, in autoimmune-prone nonobese diabetic (NOD) mice. Antigen presentation by DCIR2+ DCs but not DEC-205+ DCs elicited tolerogenic CD4+ T-cell responses in NOD mice. &beta;-Cell antigen delivered to DCIR2+ DCs delayed diabetes induction and induced increased T-cell apoptosis without interferon-&gamma; (IFN-&gamma;) or sustained expansion of autoreactive CD4+ T cells. These divergent responses were preceded by differential gene expression in T cells early after in vivo stimulation. Zbtb32 was higher in T cells stimulated with DCIR2+ DCs, and overexpression of Zbtb32 in T cells inhibited diabetes development, T-cell expansion, and IFN-&gamma; production. Therefore, we have identified DCIR2+ DCs as capable of inducing antigen-specific tolerance in the face of ongoing autoimmunity and have also identified Zbtb32 as a suppressive transcription factor that controls T cell&ndash;mediated autoimmunity.

No MeSH data available.


Related in: MedlinePlus