Self-antigen-Driven Activation Induces Instability of Regulatory T Cells during an Inflammatory Autoimmune Response

Bailey-Bucktrout, Samantha L.; Martínez‐Llordella, Marc; Zhou, X. Y.; Anthony, Bryan A.; Rosenthal, Wendy; Luche, Hervé; Fehling, Hans Jöerg; Bluestone, Jeffrey A.

doi:10.1016/j.immuni.2013.10.016

Cited by 320 publications

(340 citation statements)

References 57 publications

(99 reference statements)

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“…Fate mapping studies in mice elegantly demonstrate that Treg can lose expression of FOXP3, but are of thymic Treg origin based on genetic marking. These studies link ex‐Treg to susceptibility to multiple sclerosis68 and RA,69 and suggest that high levels of IL6 can induce this loss of FOXP3 expression in vivo . A contributing factor may be reduced IL2 signalling, which is in part mediated by SOCS1 70.…”

Section: Foxp3 Epigenetic Regulationmentioning

confidence: 85%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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Section: Foxp3 Epigenetic Regulationmentioning

confidence: 85%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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“…In mice, the majority of Tregs are stable during immune homeostasis; however, in certain inflammatory conditions Treg instability is observed (9,11,(44)(45)(46). The role of the IL-2 axis in this process is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Treg-mediated suppression is a vital negative regulator of immune-mediated inflammation, and Treg dysfunction is implicated in autoimmune and autoinflammatory disease (7,8). Loss of Treg lineage identity and subsequent development of a proinflammatory function by FOXP3 + cells has been proposed as a driver in the development of autoimmune pathologies (9)(10)(11).…”

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confidence: 99%

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

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“…Therefore, it stands to reason that unique microenvironments that are created in these diseases may instigate T cell reprogramming or that reprogrammed T cells may contribute to disease pathology. Indeed, in each of the examples described above, reprogrammed T cells could contribute to mouse models of the human diseases 13,26,71,[167][168][169] . In addition, in mouse models of multiple sclerosis and inflammatory bowel disease, the transition of T H 17 cells to a T H 1 or mixed T H 17/T H 1 cell phenotype is necessary to drive the disease 19,25,122,170,171 .…”

Section: Micrornasmentioning

confidence: 99%

“…Although dispensable for the persistence of memory T helper cells, T Reg cells (perhaps as a consequence of self-antigen recognition) seem to be constitutively activated and require interactions through their TCR and CD28 to maintain effector populations [66][67][68][69][70] . However, strong TCR stimulation of T Reg cells by an autoantigen that instigates autoimmune disease can transiently destabilize their FOXP3 expression 71 , whereas the chronic stimulation of autoreactive effector T cells may induce FOXP3 expression in these cells and promote immune tolerance 72 .…”

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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Self-antigen-Driven Activation Induces Instability of Regulatory T Cells during an Inflammatory Autoimmune Response

Cited by 320 publications

References 57 publications

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

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

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