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Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation

Cellular & Molecular Immunology 2019年第2期16卷 138-153页

作者： Prabhakaran Kumar alejandra marinelarena Divya Raghunathan Vandhana K Ragothaman Shikha Saini Palash Bhattacharya Jilao Fan Alan L Epstein Ajay V Maker Bellur S Prabhakar Department of Microbiology and Immunology University of Illinois-College of MedicineChicagoILUSA Department of Pathology University of Southern California Keck School of MedicineLos AngelesCAUSA Department of Surgery Division of Surgical OncologyUniversity of Illinois-College of MedicineChicagoILUSA

Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of *** Tregs generated in the thymus substantially contribute to the Treg pool in the periphery,where they suppress self-reactive effector T cells(Teff)***,we showed that OX40L(TNFSF4)is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation(CAP-independent)in the presence of low-dose ***,we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg(tTreg)*** of tTregs is a two-step process:Strong T-cell receptor(TCR)signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection,followed by a TCR-independent phase of tTreg development in which their maturation is driven by ***,we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg ***40−/−mice had significantly reduced numbers of CD25−Foxp3low tTreg precursors and CD25+Foxp3+mature tTregs,while OX40L treatment of WT mice induced significant proliferation of these cell *** to tTeff cells,OX40 was expressed at higher levels in both murine and human tTreg precursors and mature *** ex vivo cultures,OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs,which was mediated through the activation of AKT-mTOR *** novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation,and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.

关键词： Thymic Tregs OX40L IL-2 Treg proliferation maturation

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