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Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool.

ABSTRACT: Current models of T cell memory implicate a critical role for IL-7 in the effector-to-memory transition, raising the possibility that IL-7 therapy might enhance vaccine responses. IL-7 has not been studied, to our knowledge, before now for adjuvant activity. We administered recombinant human IL-7 (rhIL-7) to mice during immunization against the male antigen HY and compared these results with those obtained from mice immunized with rhIL-2 and rhIL-15. Administration of rhIL-7 or rhIL-15, but not rhIL-2, increased effector cells directed against these dominant antigens and dramatically enhanced CD8(+) effectors to subdominant antigens. The mechanisms by which the cytokines augmented effector pool generation were multifactorial and included rhIL-7-mediated costimulation and rhIL-15-mediated augmentation of the proliferative burst. The contraction phase of the antigen-specific response was exaggerated in cytokine-treated mice; however, CD8(+) memory pools in rhIL-7- or rhIL-15-treated groups demonstrated superior long-term survival resulting in quantitative advantages that remained long after the cytokines were discontinued, as demonstrated by improved survival after challenge with an HY-expressing tumor undertaken several weeks after cytokine cessation. These results confirm the adjuvant activity of rhIL-15 and demonstrate that rhIL-7 also serves as a potent vaccine adjuvant that broadens immunity by augmenting responses to subdominant antigens and improving the survival of the CD8(+) T cell memory pool.

SUBMITTER: Melchionda F

PROVIDER: S-EPMC1074679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells.

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The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development.

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Project description:IL-27 is an anti-inflammatory cytokine that triggers enhanced antitumor immunity, particularly cytotoxic T lymphocyte responses. In the present study, we sought to develop IL-27 into a therapeutic adjutant for adoptive T cell therapy using our well-established models. We have found that IL-27 directly improved the survival status and cytotoxicity of adoptive OT-1 CD8+ T cells in vitro and in vivo. Meanwhile, IL-27 treatment programs memory T cell differentiation in CD8+ T cells, characterized by upregulation of genes associated with T cell memory differentiation (T-bet, Eomes, Blimp1, and Ly6C). Additionally, we engineered the adoptive OT-1 CD8+ T cells to deliver IL-27. In mice, the established tumors treated with OT-1 CD8+ T-IL-27 were completely rejected, which demonstrated that IL-27 delivered via tumor antigen-specific T cells enhances adoptive T cells' cancer immunity. To our knowledge, this is the first application of CD8+ T cells as a vehicle to deliver IL-27 to treat tumors. Thus, this study demonstrates IL-27 is a feasible approach for enhancing CD8+ T cells' antitumor immunity and can be used as a therapeutic adjutant for T cell adoptive transfer to treat cancer.

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