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Configuration-dependent Presentation of Multivalent IL-15:IL-15Ralpha Enhances the Antigen-specific T Cell Response and Anti-tumor Immunity

  1. Author:
    Hong, E.
    Usiskin, I. M.
    Bergamaschi, C.
    Hanlon, D. J.
    Edelson, R. L.
    Justesen, S.
    Pavlakis, G. N.
    Flavell, R. A.
    Fahmy, T. M.

  2. Author Address

    From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511.;the Vaccine Branch, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, and.;Dermatology, Yale University School of Medicine, New Haven, Connecticut 06510.;the Department of Science, University of Copenhagen, Copenhagen 1017, Denmark.;the Departments of Immunobiology and.;From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, the Departments of Immunobiology and tarek.fahmy@yale.edu.
    1. Year: 2016
    2. Date: 22-Apr
    3. Epub Date: 1/1/2016
  2. Journal: The Journal of biological chemistry
    1. 291
    2. 17
    3. Pages: 8931-50
  4. Type of Article: Article
  5. ISSN: 0021-9258 (Print);0021-9258
  1. Abstract:

    Here we report a "configuration-dependent" mechanism of action for IL-15:IL-15Ralpha (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15:IL-15Ralpha molecules are presented to target cells significantly affects its function as a vaccine adjuvant. Although the cellular mechanism of IL-15 trans-presentation via IL-15Ralpha and its importance for IL-15 function have been described, the full effect of the IL-15:IL-15Ralpha configuration on responding cells is not yet known. We found that trans-presenting IL-15:IL-15Ralpha in a multivalent fashion on the surface of antigen-encapsulating nanoparticles enhanced the ability of nanoparticle-treated dendritic cells (DCs) to stimulate antigen-specific CD8(+) T cell responses. Localization of multivalent IL-15:IL-15Ralpha and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15:IL-15Ralpha-coated nanoparticles displayed higher levels of functional IL-15 on the cell surface, implicating a mechanism for nanoparticle-mediated transfer of IL-15 to the DC surface. Using artificial antigen-presenting cells to highlight the effect of IL-15 configuration on DCs, we showed that artificial antigen-presenting cells presenting IL-15:IL-15Ralpha increased the sensitivity and magnitude of the T cell response, whereas IL-2 enhanced the T cell response only when delivered in a paracrine fashion. Therefore, the mode of cytokine presentation (configuration) is important for optimal immune responses. We tested the effect of configuration dependence in an aggressive model of murine melanoma and demonstrated significantly delayed tumor progression induced by IL-15:IL-15Ralpha-coated nanoparticles in comparison with monovalent IL-15:IL-15Ralpha. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15:IL-15Ralpha-coated nanoparticles for antigen delivery.

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  2. DOI: 10.1074/jbc.M115.695304
  3. PMID: 26719339
  4. PMCID: PMC4861462

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