Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice

Bending, David; Peña, Hugo De La; Veldhoen, Marc; Phillips, Jenny; Uyttenhove, Catherine; Stockinger, Brigitta; Cooke, Anne

doi:10.1172/jci37865

Cited by 488 publications

(492 citation statements)

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“…The role of Th17 cells in diabetes remains unclear. Indeed the induction of the disease in NOD SCID mice after transfer of in vitro polarized Th17 anti-islet T cells was abolished by anti-IL-17 treatment in one study but not in two others [25,26]. It has been reported that IL-17-producing gdT cells do not exacerbate diabetes upon co-transfer into NOD/SCID mice [35].…”

Section: Discussionmentioning

confidence: 95%

“…Transfer of in vitro polarized BDC2.5 Th17 cells into NOD SCID mice induced diabetes in recipient mice with similar rates of onset as transfer of Th1 cells [24][25][26]. However, the exact role of IL-17 in the pathogenesis of type 1 diabetes remains unclear as the neutralization of IL-17 inhibited the disease transfer in one of the studies but not in two others.…”

Section: Introductionmentioning

confidence: 98%

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NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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“…Downregulation of the antiapoptotic gene BCL-2 (37) was seen as well as increased apoptosis of human islet cells and mouse insulinoma cells when treated with IL-17 together with other inflammatory cytokines, such as IL-1b and IFN-g. Accordingly, the synergistic effect of IFN-g and IL-17 in the induction of inflammation and apoptosis in the human islet cells indeed suggests that the coproducers of IL-17 and IFN-g might be of clinical importance, as implicated in animal models of autoimmune diabetes (3,5). Interestingly, IL-17 secretion has been reported in glutamic acid decarboxylase-specific T cell clones (38), which provides a link to the pathogenesis of T1D.…”

Section: Discussionmentioning

confidence: 98%

“…The inhibition of Th17 cells reduced islet-specific inflammatory T cell infiltration and increased the proportion of Foxp3-positive cells around the islets. In another model of autoimmune diabetes, highly purified Th17 cells from BDC2.5 mice, expressing transgenic TCR with specificity for an islet cell Ag, caused diabetes in NOD/SCID recipients (3). In this model, Th17 cells converted into Th1-like cells to secrete IFN-g, and anti-IL-17 did not prevent disease.…”

mentioning

confidence: 98%

IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

259

214

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Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-γ–secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17–positive T cells appeared to be CD4+ cells expressing TCR-αβ and CCR6, and a subpopulation showed coproduction of IFN-γ. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.

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“…In the metastable state, individual human or mouse T cells, assessed directly ex vivo, can co-express many polarizing transcription factors, cytokines and chemokine receptors [13][14][15] . Reprogramming between distinct CD4 + T cell subsets can be observed in human and mouse T cells under certain conditions in vitro [16][17][18][19] or in mice in vivo on transferring highly purified popu lations of cells [20][21][22][23][24][25] . By using lineage-tracing systems in mice, in which cells are engineered to express Cre recombinase under the control of transcriptional elements that regulate key polarization factors (such as cytokines or transcription factors) and a fluorescent protein reporter of Cre activity, endogenously polarized CD4 + T cells from many subsets have been found to change phenotype during their lifespan [26][27][28][29] .…”

mentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice

Cited by 488 publications

References 43 publications

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

IL-17 Immunity in Human Type 1 Diabetes

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

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