title: Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion.
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.
authors.affiliation: 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.
authors.forename: Scott M
authors.identifier: 0000-0002-1590-7401
authors.initials: SM
authors.lastname: Anthony
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Sarai C
authors.identifier: 0000-0002-6432-5600
authors.initials: SC
authors.lastname: Rivas
authors.affiliation: Department of Immunology, University of Connecticut Health Science Center, Farmington, CT 06030.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Colpitts
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Howard
authors.affiliation: 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.
authors.forename: Spencer W
authors.identifier: 0000-0003-4540-3279
authors.initials: SW
authors.lastname: Stonier
authors.affiliation: 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 kschluns@mdanderson.org.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D019409:Interleukin-15