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A role for interleukin-2 trans-presentation in dendritic cell–mediated T cell activation in humans, as revealed by daclizumab therapy

Nature Medicine volume 17, pages 604–609 (2011)Cite this article

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Abstract

Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells.

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Figure 1: Antigen-specific T cell proliferation in DC–T cell cocultures is profoundly inhibited by daclizumab.
Figure 2: Selective blockade of CD25 on mDCs abrogates T cell proliferation.
Figure 3: T cells do not need CD25 expression to proliferate if primed by CD25+ mDCs.
Figure 4: DCs do not express the β-chain of IL-2R and therefore do not signal in response to IL-2.
Figure 5: mDCs use their surface expression of CD25 to trans-present IL-2 to CD25− T cells (a) Phosphorylation of STAT5 in Flu-HA306–318-specific T cells (TCL) selectively pretreated with daclizumab (DacT) or control Ab (T) and co-incubated with autologous, CD25-expressing mDCs pulsed with 1 μM cognate (Flu-mDC) or noncognate (MBP83–99; MBP-mDC) peptide.
Figure 6: mDCs and T cells secrete IL-2 after antigen-specific interactions.

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Acknowledgements

The study was supported by the intramural research program of the NINDS/NIH. We thank A. Kashani for expert technical assistance in processing apheresis samples and M. Lenardo, W. Leonard and H. McFarland for their critical review of the manuscript and helpful comments. Additionally, we are thankful to M. Lenardo and H. Su (NIH) for providing cryopreserved peripheral blood mononuclear cells (PBMCs) from the CD25− individual. Daclizumab Fab was provided by Abbott Biotherapeutics, under Material Transfer Agreement.

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  1. bibi.bielekova@nih.gov

Authors and Affiliations

  1. Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA

    Simone C Wuest, Jehad H Edwan, Jayne F Martin, Sungpil Han, Justin S A Perry, Casandra M Cartagena, Eiji Matsuura & Bibiana Bielekova

  2. School of Medicine, Pusan National University, Yangsan, South Korea

    Sungpil Han

  3. Flow Cytometry Core Facility, NINDS, NIH, Bethesda, Maryland, USA

    Dragan Maric

  4. Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA

    Thomas A Waldmann

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Contributions

B.B. developed the concept of the study and supervised the project. B.B. and T.A.W. designed the experiments. S.C.W., J.F.M., S.H., J.S.A.P., C.M.C., D.M., J.E., E.M. and B.B. performed the experiments and analyzed the data. B.B., S.C.W., J.F.M., S.H. and C.M.C. wrote the paper. All authors approved the final version of this paper.

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Competing interests

B.B. and T.A.W. are co-inventors on US National Institutes of Health patents related to the use of daclizumab in multiple sclerosis and as such have received patent royalty payments.

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Wuest, S., Edwan, J., Martin, J. et al. A role for interleukin-2 trans-presentation in dendritic cell–mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med 17, 604–609 (2011). https://doi.org/10.1038/nm.2365

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