Configuration-dependent Presentation of Multivalent IL-15: IL-15Rα enhances the antigen-specific T cell response and anti-tumor immunity

TY - JOUR

T1 - Configuration-dependent Presentation of Multivalent IL-15

T2 - IL-15Rα enhances the antigen-specific T cell response and anti-tumor immunity

AU - Hong, Enping

AU - Usiskin, Ilana M.

AU - Bergamaschi, Cristina

AU - Hanlon, Douglas J.

AU - Edelson, Richard L.

AU - Justesen, Sune

AU - Pavlakis, George N.

AU - Flavell, Richard A.

AU - Fahmy, Tarek M.

PY - 2016/4/22

Y1 - 2016/4/22

N2 - Here we report a "configuration-dependent" mechanism of action for IL-15: IL-15Rα (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15: IL-15Rα 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-15Rα and its importance for IL-15 function have been described, the full effect of the IL-15: IL15Rα configuration on responding cells is not yet known. We found that trans-presenting IL-15: IL-15Rα 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-15Rα and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15: IL-15Rαcoated 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-15Rα 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: IL15Rα-coated nanoparticles in comparison with monovalent IL-15: IL-15Rα. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15: IL-15Rα-coated nanoparticles for antigen delivery.

AB - Here we report a "configuration-dependent" mechanism of action for IL-15: IL-15Rα (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15: IL-15Rα 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-15Rα and its importance for IL-15 function have been described, the full effect of the IL-15: IL15Rα configuration on responding cells is not yet known. We found that trans-presenting IL-15: IL-15Rα 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-15Rα and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15: IL-15Rαcoated 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-15Rα 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: IL15Rα-coated nanoparticles in comparison with monovalent IL-15: IL-15Rα. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15: IL-15Rα-coated nanoparticles for antigen delivery.

U2 - 10.1074/jbc.m115.695304

DO - 10.1074/jbc.m115.695304

M3 - Journal article

C2 - 26719339

SN - 0021-9258

VL - 291

SP - 8931

EP - 8950

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 17

ER -