Abstract
Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / physiology*
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Child
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Child, Preschool
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Female
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Humans
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Immunotherapy
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Infant
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Infant, Newborn
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Interleukin-15 / genetics
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Interleukin-15 / immunology*
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Interleukin-15 / metabolism
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Interleukin-2 / genetics
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Interleukin-2 / immunology*
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Interleukin-2 / metabolism
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MAP Kinase Signaling System / physiology*
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Male
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Neoplasms / genetics
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Neoplasms / immunology
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Neoplasms / metabolism
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Neoplasms / therapy
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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Receptors, Antigen, T-Cell, gamma-delta / immunology*
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Receptors, Antigen, T-Cell, gamma-delta / metabolism
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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Eomes protein, mouse
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IL15 protein, human
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IL2 protein, human
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Interleukin-15
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Interleukin-2
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Receptors, Antigen, T-Cell, gamma-delta
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T-Box Domain Proteins
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T-box transcription factor TBX21