IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes

Peluso, Ilaria; Fantini, Massimo; Fina, Daniele; Caruso, Roberta; Boirivant, Monica; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.4049/jimmunol.178.2.732

Cited by 266 publications

(229 citation statements)

References 27 publications

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“…IL-21 made a particularly attractive candidate for driving the difference, given its overexpression in NOD Tconv cells and its growth-enhancing properties (33). In addition, Peluso et al reported that IL-21 renders human CD4 ϩ CD25 Ϫ T cells refractory to in vitro suppression (34). IL21 maps to the idd3 diabetes-susceptibility region, and we confirmed that the higher IL-21 expression in NOD Tconv cells (23,30,31) was indeed a function of that locus, as NOD.idd3 b/b congenic mice exhibited the same low level of IL-21 transcripts as did B6g7 mice according to reverse transcriptase-polymerase chain reaction (RT-PCR) quantification (data not shown).…”

Section: Conventional T Cells ͉ Regulatory T Cells ͉ Type 1 Diabetesmentioning

confidence: 99%

The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors

D’Alise

Auyeung

Feuerer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

172

170

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FoxP3 ؉ regulatory T cells (Tregs) protect against autoimmunity, type 1 diabetes (T1D) in particular, prompting the hypothesis that a deficiency in Tregs is a critical determinant of diabetes susceptibility in NOD mice. However, tests of this hypothesis have yielded contradictory results. We confirmed that NOD mice, compared with reference strains, do not have a primary deficit in Treg numbers in the lymphoid organs, whether in prediabetic mice of any age or in animals with recent-onset diabetes. NOD Tregs did show a defect in standard in vitro T cell suppression assays, particularly at low suppressor/effector ratios. Gene expression profiling revealed the vast majority of transcripts constituting the ''Treg signature'' to be normally distributed in NOD Tregs versus CD4 ؉ T conventional (Tconv) cells, although there were a few differences affecting one or the other population. According to results from criss-cross experiments, the functional inefficacy was not rooted in NOD Tregs, which suppressed as well as their C57BL/6 (B6) counterparts, but rather in NOD Tconv, which were less prone to suppression than were B6 Tconv cells. They also responded more effectively to anti-CD3/28 monoclonal antibody (mAb) stimulation in vitro or to a natural pancreatic antigen in vivo. This difference was independent of autoimmune inflammation, did not map to the idd3 region, and was not due to the overproduction of interleukin-21 in NOD mice. That the immune dysregulation in this T1D model is rooted in the ability of effector T cells to be regulated, rather than in Tregs themselves, has implications for proposed therapeutic interventions.conventional T cells ͉ regulatory T cells ͉ type 1 diabetes

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Section: Conventional T Cells ͉ Regulatory T Cells ͉ Type 1 Diabetesmentioning

confidence: 99%

The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors

D’Alise

Auyeung

Feuerer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

172

170

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“…A further manner in which IL-21 may contribute to autoimmunity is by imparting resistance to T reg suppression. Several investigators have shown that IL-21 is able to counteract the suppressive function of T reg [77,87] and that this requires the IL-21 to act on conventional CD4 T cells [85,88], rather than the T reg themselves. Interestingly, resistance to T reg suppression has been reported in both mice [77] and humans with T1D [89,90], although many other factors in addition to IL-21 are likely to contribute to this effect [91].…”

Section: Possible Roles For Il-21 In Autoimmune Diabetesmentioning

confidence: 99%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

155

113

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SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

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“…For example, IL-21 induces the production of tissue-degrading matrix metalloproteinases from intestinal fibroblasts, 56 stimulates the synthesis of the T-cell chemoattractant macrophage inflammatory protein-3a (MIP-3a)/CCL20 from colonic epithelial cells, 57 renders CD25 ) CD4 + T cells resistant to Treg-mediated suppression, 58,59 and in some cases enhances IFN-c production from T cells and natural killer (NK) cells 60,61 (Table 2). Moreover, T-cell-derived IL-21 is thought to act in an autocrine fashion to induce Th17 cells.…”

Section: Interleukin-23 Has Broad Effects On Both T Cells and Non-t Cmentioning

confidence: 99%

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

2011

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Summary Interleukin‐23 (IL‐23) plays an essential role in driving intestinal pathology in experimental models of both T‐cell‐dependent and innate colitis. Furthermore, genome‐wide association studies have identified several single‐nucleotide polymorphisms in the IL‐23 receptor (IL‐23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4+ T helper 17 (Th17) cells, IL‐23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T‐cell activity and inducing the expression of Th17‐type cytokines from non‐T‐cell sources. Here we focus on Th17 cells and their associated cytokines IL‐17A, IL‐17F, IL‐21 and IL‐22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue‐protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL‐17 expression and turn on interferon‐γ production to become Th1‐like ‘ex‐Th17’ cells. Interleukin‐23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL‐23 promotes pathology in the intestinal tract. These ‘ex‐Th17’ cells may contribute to disease pathogenesis through their secretion of pro‐inflammatory mediators.

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IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes

Cited by 266 publications

References 27 publications

The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors

The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors

CD4 T cell differentiation in type 1 diabetes

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

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