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Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion

Scott M. Anthony, Sarai C. Rivas, Sara L. Colpitts, Megan E. Howard, Spencer W. Stonier and Kimberly S. Schluns
J Immunol April 22, 2016, 1600219; DOI: https://doi.org/10.4049/jimmunol.1600219
Scott M. Anthony
*Immunology Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
†Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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Sarai C. Rivas
†Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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Sara L. Colpitts
‡Department of Immunology, University of Connecticut Health Science Center, Farmington, CT 06030
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Megan E. Howard
†Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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Spencer W. Stonier
*Immunology Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
†Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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Kimberly S. Schluns
*Immunology Graduate Program, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
†Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and
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Abstract

Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG−/− mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on type I IFNs. The stimulator of IFN genes pathway was discovered to be a potent inducer of sIL-15 complexes and was required for optimal production of sIL-15 complexes in response to Ab-mediated T cell depletion and TBI, suggesting products of cell death drive production of sIL-15 complexes after lymphodepletion. Lastly, we provide evidence that IL-15 induced by inflammatory signals in response to lymphodepletion drives lymphocyte responses, as memory CD8 T cells proliferated in an IL-15–dependent manner. Overall, these studies demonstrate that the form in which IL-15 is expressed, its kinetics and cellular sources, and the inflammatory signals involved are differentially dictated by the manner in which lymphopenia is induced.

Footnotes

  • This work was supported by National Institutes of Health Predoctoral Training Grant CA009598 (to S.M.A. and S.W.S.), Postdoctoral Fellowship PF-11-152-01-LIB from the American Cancer Society (to S.L.C.), and a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center and MD Anderson Bridge funding (to K.S.S.).

  • The online version of this article contains supplemental material.

  • Received February 4, 2016.
  • Accepted March 28, 2016.
  • Copyright © 2016 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (8)
The Journal of Immunology
Vol. 206, Issue 8
15 Apr 2021
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Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion
Scott M. Anthony, Sarai C. Rivas, Sara L. Colpitts, Megan E. Howard, Spencer W. Stonier, Kimberly S. Schluns
The Journal of Immunology April 22, 2016, 1600219; DOI: 10.4049/jimmunol.1600219

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Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion
Scott M. Anthony, Sarai C. Rivas, Sara L. Colpitts, Megan E. Howard, Spencer W. Stonier, Kimberly S. Schluns
The Journal of Immunology April 22, 2016, 1600219; DOI: 10.4049/jimmunol.1600219
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