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Signaling through OX40 (CD134) breaks peripheral T-cell tolerance

Nature Medicine volume 7, pages 907–912 (2001)Cite this article

Abstract

Peripheral T-cell tolerance is a mechanism to limit autoimmunity, but represents a major obstacle in diseases such as cancer. Tolerance is due to limited accumulation of antigen-specific T cells accompanied by functional hypo-responsiveness, and is induced by antigen encounter in a non-inflammatory environment. In contrast to advances in preventing induction of T-cell tolerance, there has been little progress in defining targets to reverse established tolerance. Here we show that signals from a single dose of an agonistic antibody against OX40 (CD134, a member of the tumor necrosis-factor family of receptors) can break an existing state of tolerance in the CD4+ T-cell compartment. OX40 signals promote T-cell expansion after the hypo-responsive phenotype is induced and restore normal functionality. These data highlight the potent costimulatory capacity of OX40, and indicate OX40 as a target for therapeutic intervention in a variety of related diseases.

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Figure 1: Tolerance induction with soluble antigen.
Figure 2: OX40 signals, provided at the time of soluble antigen exposure, promote T-cell expansion and prevent induction of hypo-responsiveness.
Figure 3: Restoration of T-cell numbers and normal function by OX40 signals provided after the induction of hypo-responsiveness.
Figure 4: Anti-OX40 reverses tolerance under conditions of limited inflammation.
Figure 5: OX40 signals allow expansion of hypo-responsive and unresponsive T cells in tolerant mice.
Figure 6: Anti-OX40 reverses the tolerant state in AE7 Th1 clones.

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Acknowledgements

This work was supported by grants to M.C. from the NIH (AI42944) and the Concern Foundation.

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  1. Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, California, USA

    Pratima Bansal-Pakala, Amha Gebre-Hiwot Jember & Michael Croft

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  1. Pratima Bansal-Pakala
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Correspondence to Michael Croft.

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Bansal-Pakala, P., Gebre-Hiwot Jember, A. & Croft, M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat Med 7, 907–912 (2001). https://doi.org/10.1038/90942

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