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Stability and Progressive Differentiation of Tfr cells are intrinsically and extrinsically controlled by Tfh programs

ABSTRACT: Follicular regulatory T (Tfr) cells restrain follicular helper T (Tfh) cell-mediated B cell responses in the germinal center (GC) reaction to optimize humoral immunity while limiting autoimmunity. The immune system partially regulates GC responses by controlling the stepwise differentiation of Tfh cells. Whether Tfr cell development requires sequential developmental stages and how the immune system regulates these processes to control humoral immunity is poorly understood. Here, we used longitudinal sampling of lymphoid organs along with fate mapping and matched single-cell RNASeq/TCRseq to assess developmental dynamics of Tfr cells. We found that Tfr cells undergo dynamic clonal expansion. During this process, Tfr cells also undergo progressive differentiation through progenitor-like, early effector, and late effector stages. Late effector Tfr cells possess inherent instability, with a propensity to lose expression of the transcription factor FoxP3 to become ExTfr cells. ExTfr have unique features and can be redeemed to become suppressive Tfr cells. Acquisition of a Tfh-like transcriptional program in Tfr cells was an intrinsic predictor of progeny instability. Extrinsically, Tfh cells enhanced late effector Tfr cell differentiation by diverting early effector Tfr cells away from a default Blimp1-expressing pathway to a Bcl6-expressing one. Moreover, Tfh induce Tcf7 in Tfr cells which promotes late effector Tfr differentiation. Together, these data indicate that Tfr cells are a dynamic and plastic cell subset, the progressive differentiation of which is controlled at later effector stages by intrinsic and extrinsic programs that work together to provide a negative feedback loop to control humoral immunity.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE306818 | GEO | 2025/10/30

REPOSITORIES: GEO

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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. This model is hosted on BioModels Database and identified by: BIOMD0000000625. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Stability and Progressive Differentiation of Tfr cells are intrinsically and extrinsically controlled by Tfh programs

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