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.
This article is featured in In This Issue, p.4421
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.
Abbreviations used in this article:
- bone marrow
- BM-derived DC
- dendritic cell
- soluble IL-15
- stimulator of IFN genes
- total body irradiation
- Received February 4, 2016.
- Accepted March 28, 2016.
- Copyright © 2016 by The American Association of Immunologists, Inc.