Abstract
IL-15 is an important cytokine involved in the survival and function of CD8(+) T cells and NK cells. IL-15 can be presented by IL-15Ralpha (IL-15RA) to bind with the shared IL-2/IL-15Rbeta and common gamma-chains, which activate signaling pathways on NK cells and CD8(+) T cells. In the present study, we characterized the function of trans-presented IL-15 on NK cells and CD8(+) T cells using TC-1 tumor cells transduced with a retrovirus encoding IL-15 linked to IL-15RA (IL-15/IL-15RA). We demonstrated that the expression of IL-15/IL-15RA on TC-1 cells led to increased percentages of tumor-infiltrating NK cells, NKT cells, and CD8(+) T cells, resulting in the inhibition of tumor growth in challenged mice. Additionally, in vivo Ab depletion experiments demonstrated that NK1.1(+) cells and CD8(+) T cells were important in this inhibition of tumor growth. Furthermore, this accumulation of immune cells and inhibition of tumor growth was abolished by a single amino acid mutation in the common gamma-chain binding site on IL-15. We also observed that IL-15/IL-15RA-transduced TC-1 cells led to the activation of STAT5 in NK and CD8(+) T cells in trans, which was abolished in the mutated IL-15/IL-15RA-transduced TC-1 cells. Taken together, our data suggest that common gamma-chain binding-dependent activation of the shared IL-15/IL-2Rbeta/common gamma signaling pathway may play an important role in the activation of NK cells and CD8(+) T cells, resulting in IL-15/IL-15RA trans-presentation-mediated inhibition of tumor growth.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen Presentation / genetics
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Antigens, Ly / biosynthesis*
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Antigens, Ly / physiology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Cell Line, Tumor
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Female
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Growth Inhibitors / biosynthesis
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Growth Inhibitors / physiology*
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Interleukin Receptor Common gamma Subunit / genetics
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Interleukin Receptor Common gamma Subunit / physiology*
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Interleukin-15 / biosynthesis
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Interleukin-15 / genetics
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Interleukin-15 / metabolism
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Interleukin-15 / physiology*
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Interleukin-15 Receptor alpha Subunit / biosynthesis
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Interleukin-15 Receptor alpha Subunit / genetics
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Interleukin-15 Receptor alpha Subunit / metabolism
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Interleukin-15 Receptor alpha Subunit / physiology
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Interleukin-2 Receptor beta Subunit / physiology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NK Cell Lectin-Like Receptor Subfamily B / biosynthesis*
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NK Cell Lectin-Like Receptor Subfamily B / physiology
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Ovarian Neoplasms / immunology
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Ovarian Neoplasms / pathology
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Ovarian Neoplasms / prevention & control*
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Ovarian Neoplasms / virology
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Retroviridae / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Transduction, Genetic
Substances
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Antigens, Ly
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Growth Inhibitors
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Il2rb protein, mouse
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Interleukin Receptor Common gamma Subunit
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Interleukin-15
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Interleukin-15 Receptor alpha Subunit
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Interleukin-2 Receptor beta Subunit
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Klrb1c protein, mouse
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NK Cell Lectin-Like Receptor Subfamily B