TFH cells progressively differentiate to regulate the germinal center response

Weinstein, Jason S.; Herman, Edward I.; Laínez, Begoña; Licona-Limón, Paula; Esplugues, Enric; Flavell, Richard A.; Craft, Joe

doi:10.1038/ni.3554

Cited by 312 publications

(361 citation statements)

References 56 publications

(88 reference statements)

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“…It is also known that IL-21 and IL-4 are key cytokines that T FH cells express during the GC response41. Because Cic f/f Vav1-Cre mice had the increased T-cell surface expression of ICOS, the increased proportions of CD4 + IFNγ + , CD4 + IL-21 + and CD4 + IL-4 + T cells, and the autoimmune-like symptoms similar to those in Roquin san mice42, we set out to determine whether the T FH subset was elevated in Cic f/f Vav1-Cre mice.…”

Section: Resultsmentioning

confidence: 99%

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Park

Lee

et al. 2017

Nat Commun

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High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null TFH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in TFH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC–ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates TFH cell development and autoimmunity.

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Section: Resultsmentioning

confidence: 99%

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Park

Lee

et al. 2017

Nat Commun

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“…Such metabolic requirement matches well with accumulation of glycolytic metabolites in SLE patients’ lymphocytes [24]. Apparently, Tfh cells are far from homogenous, as they can produce not only IL-21 but also IL-17 [29•] and IL-4 [30•]. Since Tfh cells are expanded in patients with severe SLE [31], the role of mTOR pathway activation would be important to precisely define in this proinflammatory T cell subset.…”

Section: Immune Systemmentioning

confidence: 94%

Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

et al. 2016

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The mechanistic target of rapamycin (mTOR) is a central regulator in cell growth, activation, proliferation, and survival. Activation of the mTOR pathway underlies the pathogenesis of systemic lupus erythematosus (SLE). While mTOR activation and its therapeutic reversal were originally discovered in T cells, recent investigations have also uncovered roles in other cell subsets including B cells, macrophages, and “non-immune” organs such as the liver and the kidney. Activation of mTOR complex 1 (mTORC1) precedes the onset of SLE and associated co-morbidities, such as anti-phospholipid syndrome (APS), and may act as an early marker of disease pathogenesis. Six case reports have now been published that document the development of SLE in patients with genetic activation of mTORC1. Targeting mTORC1 over-activation with N-acetylcysteine, rapamycin, and rapalogs provides an opportunity to supplant current therapies with severe side effect profiles such as prednisone or cyclophosphamide. In the present review, we will discuss the recent explosion of findings in support for a central role for mTOR activation in SLE.

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“…A newer IL-21 fluorescent protein reporter mouse model observed robust stability of IL-21 + CXCR5 + T FH CD4 T cells after transfers into new hosts, but did not test memory time points (Weinstein et al 2016). In the context of an acute LCMV infection, memory CD4 T cells appear to largely maintain their T H 1 or T FH programming upon 2˚response.…”

Section: Plasticity When Memory Cd4 T Cells Are Recalled?mentioning

confidence: 99%

Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

Crotty

2017

Cold Spring Harb Perspect Biol

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Plasticity is the ability of a cell type to convert to another cell type. There are multiple effector CD4 T-cell subtypes, including T1, T2, T17, T1*, CD4 CTL, T9, and T cells. It is commonly thought that a CD4 T cell can readily show full plasticity-full conversion from one differentiated cell-and this propensity to plasticity is possessed by memory CD4 T cells. However, there remains no direct demonstration of in vivo-generated resting memory CD4 T-cell conversion to a different subtype on secondary antigen challenge in vivo in an intact animal at the single-cell level. What has been clearly shown is that CD4 T cells possess extraordinary capacity for phenotypic heterogeneity, but that is a distinct property from plasticity. Heterogeneity is diversity of the resting memory CD4 T-cell population, not conversion of a single differentiated cell into another subtype. Apparently, plasticity at the population level can be accomplished by either mechanism, as heterogeneity of CD4 T-cell subpopulations could affect large shifts in subtype distribution at the overall population level via differential exponential expansion and death.

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TFH cells progressively differentiate to regulate the germinal center response

Cited by 312 publications

References 56 publications

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

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