Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6

Gao, Wenda; Thompson, Lorraine; Zhou, Qiang; Putheti, Prabhakar; Fahmy, Tarek M.; Strom, Terry B.; Metcalfe, Su

doi:10.4161/cc.8.9.8348

Cited by 111 publications

(123 citation statements)

References 27 publications

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“…58 A potential role of increased levels of IL-6 in human kidney graft rejection has been suggested 59 andgiven the opposing reciprocity between LIF and IL-6 as detailed later 34 -this may relate to the finding of a correlation between enhanced IL-6 signalling and poor primary kidney graft function in the clinic. 60 LIF delivered to CD4 þ cells via biodegradable PLGA nanoparticles guided the in vivo alloimmune response toward CD4 þ Foxp3 þ Treg, while treatment with anti-LIF had the opposite effect 34 demonstrating an allospecific, LIF-specific, effect. This places LIF at odds with IL-6 in terms of T-cell function, IL-6 being pro-inflammatory and a driver of TH17 lineage development in the presence of transforming growth factor-b.…”

Section: Lif In T Cellsmentioning

confidence: 99%

“…Un-stimulated naive T cells show very low gp130 and gp190 surface expression, but activation results in conversion to a gp130 high gp190 high phenotype within 48 h. 34 The commonality of the gp130 receptor subunit for both LIF and IL-6, versus the specificity of the gp190 subunit for LIF, would be permissive for receptor competition should gp190 become effectively high and gp130 become limiting. Accordingly, it has been suggested that regulation of gp190 may contribute to a mechanism to favour LIF signalling over IL-6 signalling in T cells.…”

Section: Background To Lif In T Lymphocyte Biologymentioning

confidence: 99%

“…Overall it was shown that the local milieu of the central nervous system (CNS) tissue conditioned by IL-6 can dramatically influence the development of both auto-antigen-specific as well as nonspecific immune responses and associated pathology. A range of possible A LIF/IL-6 axis is linked to Treg versus TH17 lineage development LIF released during the ex vivo allo-tolerant response to donor was found to be associated with profound repression of INFg release and delayed kinetics of IL-6 release; 34,67 in marked contrast, in allo-rejection, LIF was low while INFg rapidly reached ngml -1 levels-over 500-fold greater when compared with allo-tolerance. 34,67 In follow-on studies, LIF was confirmed to induce specific suppression of INFg release following stimulation by Tcell mitogens.…”

Section: Lif In T Cellsmentioning

confidence: 99%

“…A range of possible A LIF/IL-6 axis is linked to Treg versus TH17 lineage development LIF released during the ex vivo allo-tolerant response to donor was found to be associated with profound repression of INFg release and delayed kinetics of IL-6 release; 34,67 in marked contrast, in allo-rejection, LIF was low while INFg rapidly reached ngml -1 levels-over 500-fold greater when compared with allo-tolerance. 34,67 In follow-on studies, LIF was confirmed to induce specific suppression of INFg release following stimulation by Tcell mitogens. 46 Other groups later showed that IL-6, known to be associated with inhibition of allo-tolerance, 68 promotes differentiation of TH17 cells in the presence of transforming growth factor-b.…”

Section: Lif In T Cellsmentioning

confidence: 99%

“…46 Other groups later showed that IL-6, known to be associated with inhibition of allo-tolerance, 68 promotes differentiation of TH17 cells in the presence of transforming growth factor-b. 61 When exploring possible interactions between LIF and IL-6, a head-to-head study revealed that LIF and IL-6 function as polar opposites in CD4 þ T cells, 34,69 as illustrated in Figure 3. LIF directly promoted the Treg lineage-specific transcription factor, Foxp3, while simultaneously repressing TH17 lineage-specific genes including the transcription factor RORgt: conversely, IL-6 inhibited expression of Foxp3 and promoted RORgt.…”

Section: Lif In T Cellsmentioning

confidence: 99%

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LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.

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Section: Lif In T Cellsmentioning

confidence: 99%

Section: Background To Lif In T Lymphocyte Biologymentioning

confidence: 99%

Section: Lif In T Cellsmentioning

confidence: 99%

Section: Lif In T Cellsmentioning

confidence: 99%

Section: Lif In T Cellsmentioning

confidence: 99%

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LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke

Jickling

Ander²,

Stamova³

et al. 2013

Annals of Neurology

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Objective Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood brain barrier is a central feature to HT pathogenesis, and leukocytes may contribute to this process. We sought to determine whether ischemic strokes that develop HT have differences in RNA expression in blood within 3 hours of stroke onset prior to treatment with thrombolytic therapy. Methods Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA assessed by microarray analysis. Strokes that developed HT (n=11) were compared to strokes without HT (n=33) and controls (n=14). Genes were identified (corrected p-value <0.05, fold change ≥|1.2|) and functional analysis performed. RNA prediction of HT in stroke was evaluated using cross-validation, and in a second stroke cohort (n=52). Results Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic therapy. A panel of 6 genes could predict strokes that later developed HT with 80% sensitivity and 70.2% specificity. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase-9; a shift in transforming growth factor-beta signaling involving SMAD4, INPP5D and IRAK3; and a disruption of coagulation factors V and VIII. Interpretation Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of the identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk.

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Changes in T‐cell subsets identify responders to FcR‐nonbinding anti‐CD3 mAb (teplizumab) in patients with type 1 diabetes

et al. 2015

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The mechanisms whereby immune therapies affect progression of Type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR non-binding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8+ central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from 2 randomized clinical studies of teplizumab in patients with new and recent onset T1D. At the conclusion of therapy clinical responders showed a significant reduction in circulating CD4+ effector memory (CD4EM) T cells. Afterwards, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non-CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and non-responders vs placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D.

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Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6

Abstract: Within the immune system there is an exquisite ability to discriminate between "self " and "non-self " that is orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (

Cited by 111 publications

References 27 publications

LIF in the regulation of T-cell fate and as a potential therapeutic

LIF in the regulation of T-cell fate and as a potential therapeutic

RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke

Changes in T‐cell subsets identify responders to FcR‐nonbinding anti‐CD3 mAb (teplizumab) in patients with type 1 diabetes

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