Chimeric γc cytokine receptors confer cytokine independent engraftment of human T lymphocytes

Michelle R Hunter; Megan E Prosser; Vaidehi Mahadev; Xiuli Wang; Brenda Aguilar; Christine E Brown; Stephen J Forman; Michael C Jensen

doi:10.1016/j.molimm.2013.03.021

Chimeric γc cytokine receptors confer cytokine independent engraftment of human T lymphocytes

Mol Immunol. 2013 Nov;56(1-2):1-11. doi: 10.1016/j.molimm.2013.03.021. Epub 2013 Apr 27.

Authors

Michelle R Hunter¹, Megan E Prosser, Vaidehi Mahadev, Xiuli Wang, Brenda Aguilar, Christine E Brown, Stephen J Forman, Michael C Jensen

Affiliation

¹ Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.

PMID: 23628622
DOI: 10.1016/j.molimm.2013.03.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
Blotting, Western
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / transplantation
Cell Proliferation / drug effects
Cells, Cultured
Flow Cytometry
Humans
Immunologic Memory / immunology
Interleukin Receptor Common gamma Subunit / deficiency
Interleukin Receptor Common gamma Subunit / genetics
Interleukin Receptor Common gamma Subunit / immunology
Interleukin-15 / immunology
Interleukin-15 / pharmacology
Interleukin-2 Receptor beta Subunit / genetics
Interleukin-2 Receptor beta Subunit / immunology*
Interleukin-2 Receptor beta Subunit / metabolism
Interleukin-7 / genetics
Interleukin-7 / immunology*
Interleukin-7 / metabolism
Jurkat Cells
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Receptors, Interleukin-7 / genetics
Receptors, Interleukin-7 / immunology*
Receptors, Interleukin-7 / metabolism
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / immunology
Recombinant Fusion Proteins / metabolism
STAT5 Transcription Factor / immunology
STAT5 Transcription Factor / metabolism
Shc Signaling Adaptor Proteins / immunology
Shc Signaling Adaptor Proteins / metabolism
Signal Transduction / immunology
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
T-Lymphocytes, Cytotoxic / transplantation
Transplantation, Heterologous

Substances

Interleukin Receptor Common gamma Subunit
Interleukin-15
Interleukin-2 Receptor beta Subunit
Interleukin-7
Receptors, Interleukin-7
Recombinant Fusion Proteins
STAT5 Transcription Factor
Shc Signaling Adaptor Proteins
interleukin-7 receptor, alpha chain