Treg functional stability and its responsiveness to the microenvironment

Barbi, Joseph; Pardoll, Drew M.; Fan, Ping

doi:10.1111/imr.12172

Cited by 196 publications

(161 citation statements)

References 258 publications

(385 reference statements)

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“…Tfh cells did not express Foxp3 in these conditions. Because IL-6 reportedly destabilizes Foxp3 expression (28) but has a role in Tfh formation, IL-6 was added to cell cultures to test the stability of the Treg subsets in adverse conditions. A partial loss of Foxp3 expression was seen; however, the most affected subset was nTreg cells.…”

Section: Cd25 − Tfr Cells Have a Gene Expression Pattern Equidistantmentioning

confidence: 99%

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Wing

Kitagawa

Locci

et al. 2017

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

170

236

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T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

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Section: Cd25 − Tfr Cells Have a Gene Expression Pattern Equidistantmentioning

confidence: 99%

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Wing

Kitagawa

Locci

et al. 2017

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

170

236

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“…Well‐characterised sensors of metabolic stimuli include mTor and HIF,73, 74 which can influence the differentiation of Treg vs effector T‐cells including Th17. These exert a network effect as they in turn regulate gene networks influencing biochemical responses including glycolysis.…”

Section: Tissue and Metabolic Cues Can Alter Transcriptional Programmmentioning

confidence: 99%

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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“…Because other members in the Tim family may substitute for Tim-3 in Tim-3-deficient mice, the hypothesis that Tim-3 may play an important positive role in the adaptive immune response should be considered. [26] . Th17 cells are a new subtype of CD4 + T cells that secrete the cytokine IL-17 [27] .…”

Section: Tim-3 and Effector T Cellsmentioning

confidence: 99%

Role of Tim-3 in hepatitis B virus infection: An overview

Liu

Gao

Liang

et al. 2016

WJG

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Hepatitis B virus (HBV) infection has received increasing public attention. hBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the abovementioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of hBV-related liver disease and suggest new therapeutic methods for intervention.

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Treg functional stability and its responsiveness to the microenvironment

Cited by 196 publications

References 258 publications

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

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

Role of Tim-3 in hepatitis B virus infection: An overview

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Treg functional stability and its responsiveness to the microenvironment

Cited by 196 publications

References 258 publications

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

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

Role of Tim-3 in hepatitis B virus infection: An overview

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A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers