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

Cellular & Molecular Immunology volume 16, pages 138–153 (2019)Cite this article

Abstract

Regulatory T cells (Tregs) play a pivotal role in immune-tolerance, and loss of Treg function can lead to the development of autoimmunity. Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery, where they suppress self-reactive effector T cells (Teff) responses. Recently, 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 IL-2. Therefore, we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg (tTreg) development. Development 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 IL-2. Therefore, we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development. OX40−/− 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 subsets. Relative to tTeff cells, OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs. In 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 signaling. These 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.

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Acknowledgements

We thank the National Institutes of Health for grants #R01 AI107516-01A1 and #1R41AI125039-01. We thank the Juvenile Diabetes Research Foundation (JDRF) for grant #2-SRA-2016-245- S-B to Dr. Prabhakar. We thank the American Heart Association for offering a post-doctoral fellowship #15POST25090228 to PK.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA

    Prabhakaran Kumar, Alejandra Marinelarena, Divya Raghunathan, Vandhana K Ragothaman, Shikha Saini, Palash Bhattacharya, Ajay V Maker & Bellur S Prabhakar

  2. Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    Alan L Epstein

  3. Department of Surgery, Division of Surgical Oncology, University of Illinois-College of Medicine, Chicago, IL, USA

    Ajay V Maker

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Kumar, P., Marinelarena, A., Raghunathan, D. et al. Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation. Cell Mol Immunol 16, 138–153 (2019). https://doi.org/10.1038/cmi.2018.8

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