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Hyperactive PI3K-delta in Th1 and Th2 differentiation

ABSTRACT: While inputs regulating CD4+ T helper cell (Th) differentiation are well-defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th-lineage identity remain incompletely resolved. PI3K signaling is a critical regulator of T-cell function; activating mutations affecting PI3Kd result in an immunodeficiency with multiple T-cell defects. Using mice expressing activated-PI3Kd, we found aberrant expression of proinflammatory Th1-signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kd-IL-2-Foxo1 signaling amplification loop, fueling Foxo1-inactivation, loss of Th2-lineage restriction and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR-signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated-PI3Kd, thereby linking two key pathways of immune dysregulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE214871 | GEO | 2023/10/04

REPOSITORIES: GEO

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Project description:Webb2002 - Fas/FasL mediated tumor T-cell interaction This deterministic model of immunological surveillance involving tumour cell–T-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. This model is described in the article: Cells behaving badly: a theoretical model for the Fas/FasL system in tumour immunology. Webb SD, Sherratt JA, Fish RG. Math Biosci 2002 Sep-Oct; 179(2): 113-129 Abstract: One proposed mechanism of tumour escape from immune surveillance is tumour up-regulation of the cell surface ligand FasL, which can lead to apoptosis of Fas receptor (Fas) positive lymphocytes. Based upon this 'counterattack', we have developed a mathematical model involving tumour cell-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. The model predicts that (a) the production of soluble forms of Fas and FasL will lead to the down-regulation of the immune response; (b) matrix metalloproteinase (MMP) inactivation should lead to increased membrane FasL and result in a higher rate of Fas-mediated apoptosis for lymphocytes than for tumour cells. Recent studies on cancer patients lend support for these predictions. The clinical implications are two-fold. Firstly, the use of broad spectrum MMP inhibitors as anti-angiogenic agents may be compromised by their adverse effect on tumour FasL up-regulation. Also, Fas/FasL interactions may have an impact on the outcome of numerous ongoing immunotherapeutic trials since the final common pathway of all these approaches is the transduction of death signals within the tumour cell. This model is hosted on BioModels Database and identified by: BIOMD0000000661. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. 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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Hyperactive PI3K-delta in Th1 and Th2 differentiation

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