Project description:T follicular helper (Tfh) cells are a specialized subset of CD4 T cells that are essential for most antibody productions and humoral responses. It is well characterized that transcriptional network exerts indispensable roles in Tfh cell differentiation. However, how post-transcriptional regulation controls Tfh biology has largely remained unclear. Multiple mice models were used here by a series of experimental approaches to illustrate m6A methyltransferase Mettl3 programs Tfh cell differentiation at post-transcriptional layer.
Project description:Follicular helper T (Tfh) cells, as important effector CD4+ T cells, are able to regulate antigen-specific B cell immunity in vivo. It is well characterized that transcription factors, cytokines, microRNA, epigenetic modifications exerts important roles in Tfh differentiation and function. Howerer, the regulatory mechanism of the major signaling pathways driving Tfh cell differentiation remains unclear. Multiple mice models were used by a series of experimental approaches to illustrate PDK1 signaling programs Tfh differentiation and function.
Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. NaM-CM-/ve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a M-bM-^@M-^XgatekeeperM-bM-^@M-^Y to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a M-bM-^@M-^\double checkM-bM-^@M-^] mechanism as fundamental regulators in Tfh cell differentiation and humoral responses. Gene expression analysis of ex vivo OT-II Foxp1-WT Tfh cells and OT-II Foxp-conditional knockout (CKO) Tfh cells 5 days after immunization.
Project description:Leber2016 - Expanded model of Tfh-Tfr
differentiation - Helicobacter pylori infection
The parameters used in the model were
obtained from experiments conducted by the authors, previous
publications [
1,
2,
3] and
parameter optimisation carried out in the paper using particle
swarm and genetic algorithms.
This model is described in the article:
Bistability analyses of CD4+
T follicular helper and regulatory cells during Helicobacter
pylori infection.
Leber A, Abedi V, Hontecillas R,
Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T,
Bassaganya-Riera J.
J. Theor. Biol. 2016 Jun; 398:
74-84
Abstract:
T follicular helper (Tfh) cells are a highly plastic subset
of CD4+ T cells specialized in providing B cell help and
promoting inflammatory and effector responses during infectious
and immune-mediate diseases. Helicobacter pylori is the
dominant member of the gastric microbiota and exerts both
beneficial and harmful effects on the host. Chronic
inflammation in the context of H. pylori has been linked to an
upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes,
controlled in part by the cytokine, interleukin-21. This study
investigates the differentiation and regulation of Tfh cells,
major producers of IL-21, in the immune response to H. pylori
challenge. To better understand the conditions influencing the
promotion and inhibition of a chronically elevated Tfh
population, we used top-down and bottom-up approaches to
develop computational models of Tfh and T follicular regulatory
(Tfr) cell differentiation. Stability analysis was used to
characterize the presence of two bi-stable steady states in the
calibrated Tfh/Tfr models. Stochastic simulation was used to
illustrate the ability of the parameter set to dictate two
distinct behavioral patterns. Furthermore, sensitivity analysis
helped identify the importance of various parameters on the
establishment of Tfh and Tfr cell populations. The core network
model was expanded into a more comprehensive and predictive
model by including cytokine production and signaling pathways.
From the expanded network, the interaction between TGFB-Induced
Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was
displayed to exert control over the determination of the Tfh
response. Model simulations predict that Tgif1 and RXR
respectively induce and curtail Tfh responses. This
computational hypothesis was validated experimentally by
assaying Tgif1, RXR and Tfh in stomachs of mice infected with
H. pylori.
The impulse of RXR as shown in the paper
(figure 7C) can be implemented by creating an event in the curated
SBML file.
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BIOMD0000000625.
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To the extent possible under law, all copyright and related or
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Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. Naïve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a ‘gatekeeper’ to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a “double check” mechanism as fundamental regulators in Tfh cell differentiation and humoral responses.
Project description:T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.
Project description:To determine the role of the cytokine activin A in the regulation of human T follicular helper (Tfh) cell gene program, we performed a transcriptomic analysis (RNA-seq) of human naïve CD4 T cells differentiated in vitro with activin A. The analysis of the gene expression profile driven by activin A, alone or in combination with IL-12 (a know regulator of human Tfh differentiation/function), revealed that activin A can regulate the expression of multiple molecules involved in the differentiation and/or function of human Tfh cells.