Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice

Ohl, Kim; Wiener, Anastasia; Schippers, Angela; Wagner, Norbert; Tenbrock, Klaus

doi:10.1111/cei.12629

Cited by 23 publications

(25 citation statements)

References 62 publications

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“…Accordingly, a recent report demonstrates that the CD25 deficiency of SLE T regs could be reversed efficiently by IL‐2 in cell cultures, as well as in patients undergoing low‐dose IL‐2 therapy . This corresponds with findings that restoring IL‐2 production in lupus‐prone mice enhanced the generation of CD25 + FoxP3 + T regs .…”

Section: Discussionsupporting

confidence: 66%

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

Costa

Marques

Godinho

et al. 2017

Clinical and Experimental Immunology

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SummaryForkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)‐2 receptor alpha chain]. Low‐dose IL‐2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE‐unaffected first‐degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25‐encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up‐regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up‐regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL‐2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up‐regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg‐directed therapies can be monitored more effectively when taking this distinction into account.

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Section: Discussionsupporting

confidence: 66%

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

Costa

Marques

Godinho

et al. 2017

Clinical and Experimental Immunology

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“…In addition, IL-21 is a central cytokine for promotion of B cell antibody production. Fas (CD95) −/− CREMα tg mice display enhanced anti-dsDNA autoantibodies and enhanced total IgG production (7, 8), which could possibly be related to this fact. Transcription of CREM itself is dependent on calcium/calmodulin-dependent protein kinase type IV (CamKIV) activation (46).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the observed effects of CREMα on IL-2 and IL-17a cytokine production in humans are also observed in transgenic mice with T cell-specific CREMα overexpression (under control of the cd2 promoter) [CREMα transgenic (tg)] (7). These mice have decreased IL-2 and increased IL-17a levels and are more prone to develop signs of autoimmunity (including lymphadenopathy and higher autoantibody titers against double-stranded DNA) when an additional genetic deletion of the cd95 gene (Fas) is present (7, 8). …”

Section: Introductionmentioning

confidence: 99%

CREM Alpha Enhances IL-21 Production in T Cells In Vivo and In Vitro

Ohl¹,

Wiener²,

Lippe³

et al. 2016

Front. Immunol.

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The cAMP-responsive element modulator alpha (CREMα) plays a role in autoimmunity and, in particular, in systemic lupus erythematosus. CREMα negatively regulates IL-2 transcription and activates IL-17 expression by direct transcriptional mechanisms. To understand the role of CREM in autoimmunity, we recently generated a mouse with a transgenic overexpression of CREMα selectively in T cells. This mouse is characterized by enhanced IL-17 and IL-21 expression. We, herein, dissect the transcriptional mechanisms of enhanced IL-21 transcription in these mice. T cells of CREMα transgenic mice display an enhanced binding of CREMα to the CD3ζ chain promoter resulting in decreased CD3ζ chain expression. This is accompanied by a decreased excitation threshold and enhanced Ca2+ influx, which is known to induce IL-21 expression via NFATc2 activation. However, CREMα directly binds to cAMP-response element (CRE) half-site within the Il-21 promoter, which results in enhanced promoter activity shown by promoter reporter assays. CREMα-induced IL-21 transcription is not abrogated in the presence of cyclosporine A but depends on an intact CRE site within the IL-21 promoter, which suggests that CREM largely enhances IL-21 expression by direct transcriptional regulation. IL-21 transcription is critical for IL-17 generation in these mice, since IL-21 receptor blockade downregulates IL-17 transcription to wild-type levels. Finally, this is of functional relevance since CREMα transgenic mice display enhanced disease activity in dextran sodium sulfate-induced colitis accompanied by higher local IL-21 expression. Thus, we describe two novel mechanisms of CREMα-dependent IL-21 transcription. Since T cells of systemic lupus erythematosus patients are characterized by enhanced IL-21 transcription, this might also be of functional relevance in humans.

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“…In SLE patients, various cytotoxic responses have been reported ineffective and may account for the increased susceptibility to infection. The inhibited Tregs are unable to prevent autoimmunity, and the deficiency in AICD may lead to extended survival of autoreactive T cells, thereby B cells overactivate, in the end, resulting in overproduction of autoantibodies and the development of SLE [30–32]. …”

Section: Introductionmentioning

confidence: 99%

“…It also represses the transcription factor c-fos, the antigen-presenting cell molecule CD86, and Notch signaling receptor Notch-1 to participate in the pathogenesis of SLE [35, 39–41]. And, the most important mechanism is that overexpressing CREMα can repress IL-2, yet increased IL-17A [32, 42]. However, which factors and mechanisms contribute to increased CREMα in SLE T cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus

et al. 2016

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BackgroundUp-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREMα expression in SLE.ResultsFrom the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREMα promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREMα mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREMα promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMα promoter and CREMα mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn’t alter greatly at the CREMα promoter. All these changes inhibited the expression of CREMα, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREMα promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREMα promoter in SLE CD4+ T cells.ConclusionsIn SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREMα promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREMα overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0294-2) contains supplementary material, which is available to authorized users.

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Interleukin-2 treatment reverses effects of cAMP-responsive element modulator α-over-expressing T cells in autoimmune-prone mice

Cited by 23 publications

References 62 publications

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

CREM Alpha Enhances IL-21 Production in T Cells In Vivo and In Vitro

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus

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