Integrative network modeling reveals mechanisms underlying T cell exhaustion
Integrative network modeling reveals mechanisms underlying T cell exhaustion
Abstract Failure to clear antigens causes CD8+ T cells to become increasingly hypo-functional, a state known as exhaustion. We combined manually extracted information from published literature with gene expression data from diverse model systems to infer a set of molecular regulatory interactions that underpin exhaustion. Topological analysis and simulation modeling of the network suggests CD8+ T cells undergo 2 major transitions in state following stimulation. The time cells spend in the earlier proliferative/pro-memory (PP) state is a fixed and inherent property of the network structure. Transition to the second state is necessary for exhaustion. Combining insights from network topology analysis and simulation modeling, we predict the extent to which each node in our network drives cells towards an exhausted state. We demonstrate the utility of our approach by experimentally testing the prediction that druginduced interference with EZH2 function increases the proportion of proliferative/pro-memory cells in the early days post-activation.
van der Vuurst de Vries Anne-Renee、Young Mary、Johnson Rebecca、Fox Brian、Huang Lu、Sivakumar Pallavur、Dervan Andrew、Bolouri Hamid、Bassett Douglas、Santini Cristina Costa、Ratushny Alexander、Shannon Paul、Beilke Joshua、Trotter Matthew、Hill Christopher Mark
Celgene CorporationCelgene CorporationCelgene CorporationCelgene CorporationCelgene Institute for Translational Research Europe (CITRE)Celgene CorporationCelgene CorporationDivision of Human Biology, Fred Hutchinson Cancer Research CenterCelgene CorporationCelgene Institute for Translational Research Europe (CITRE)Celgene CorporationInstitute for Systems BiologyCelgene CorporationCelgene Institute for Translational Research Europe (CITRE)Celgene Corporation
基础医学生物科学研究方法、生物科学研究技术分子生物学
van der Vuurst de Vries Anne-Renee,Young Mary,Johnson Rebecca,Fox Brian,Huang Lu,Sivakumar Pallavur,Dervan Andrew,Bolouri Hamid,Bassett Douglas,Santini Cristina Costa,Ratushny Alexander,Shannon Paul,Beilke Joshua,Trotter Matthew,Hill Christopher Mark.Integrative network modeling reveals mechanisms underlying T cell exhaustion[EB/OL].(2025-03-28)[2025-08-31].https://www.biorxiv.org/content/10.1101/582312.点此复制
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