Abstract
Therapeutic responses following adoptive transfer of T cells correlate to levels of long-term T cell persistence. Lymphodepletion and exogenous γc cytokine administration can improve T cell persistence following adoptive transfer, but their effects are not uniform and toxicities are significant. To overcome these limitations, we designed a chimeric γc cytokine receptor (CγCR) composed of Interleukin-7 (IL-7) tethered to IL-7Rα/CD127 that confers exogenous cytokine independent, cell intrinsic, STAT5 cytokine signals. We additionally show that this design is modular in that the IL-2Rβ/CD122 cytoplasmic chain can be exchanged for that of IL-7Rα/CD127, enhancing Shc activity. When expressed in central memory-derived primary human CD8(+) CTL (T(E/CM)), these CγCRs signal according to their corresponding wild-type counterparts to support exogenous cytokine independent viability and homeostatic proliferation, while retaining full effector function. In vivo studies demonstrate that both CγCR-CD127(+) and CγCR-CD122(+) CD8(+) T((E/CM)) engraft in mice and persist in an absence of exogenous cytokine administration. Engrafted CγCR-CD127(+) CD8(+) T(E/CM) preferentially retain central memory marker expression in vivo demonstrating a dichotomy between CD127 versus CD122 signaling. Together, these results suggest that expression of CγCR in therapeutic T cells may aid in the in vivo persistence of these cells, particularly under conditions of limiting homeostatic cytokines.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Blotting, Western
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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 / transplantation
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Cell Proliferation / drug effects
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Cells, Cultured
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Flow Cytometry
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Humans
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Immunologic Memory / immunology
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Interleukin Receptor Common gamma Subunit / immunology
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Interleukin-15 / immunology
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Interleukin-15 / pharmacology
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Interleukin-2 Receptor beta Subunit / genetics
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Interleukin-2 Receptor beta Subunit / immunology*
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Interleukin-2 Receptor beta Subunit / metabolism
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Interleukin-7 / genetics
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Interleukin-7 / immunology*
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Interleukin-7 / metabolism
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Jurkat Cells
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Receptors, Interleukin-7 / genetics
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Receptors, Interleukin-7 / immunology*
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Receptors, Interleukin-7 / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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STAT5 Transcription Factor / immunology
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STAT5 Transcription Factor / metabolism
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Shc Signaling Adaptor Proteins / immunology
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Shc Signaling Adaptor Proteins / metabolism
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Signal Transduction / immunology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / transplantation
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Transplantation, Heterologous
Substances
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Interleukin Receptor Common gamma Subunit
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Interleukin-15
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Interleukin-2 Receptor beta Subunit
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Interleukin-7
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Receptors, Interleukin-7
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Recombinant Fusion Proteins
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STAT5 Transcription Factor
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Shc Signaling Adaptor Proteins
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interleukin-7 receptor, alpha chain