Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT.
The outcome of umbilical cord blood transplantation (UCBT) is compromised by low hematopoietic stem cell (HSC) doses leading to prolonged time to engraftment, delayed immunological reconstitution and late memory T-cell skewing. Exposure of UCB to dimethyl-prostaglandin E2 (dmPGE2) increases HSC in vivo. We determined that exposure of UCB T lymphocytes to dmPGE2 modified Wnt signaling resulting in T cell factor (TCF)-mediated transcription. Wnt signaling upregulated interleukin (IL)-7R and IL-2Rβ, resulting in enhanced survival mediated by the homeostatic cytokines IL-7 and IL-15. dmPGE2 also induced components of the Wnt pathway and Wnt receptors, thereby priming UCB T cells to receive signals via Wnt ligands in vivo. We observed that the Wnt transcription factor TCF7 and its target EOMES were elevated in the T cells of patients who received PGE2-treated UCBs. Consistent with the role of Wnt/β-catenin signaling to induce and maintain naive, memory precursors and long-lived central memory CD8(+) cells, these patients also had increased fractions of CD8(+)CD45RO(-)CD62L(+) plus CD8(+)CD45RO(+)CD62L(+) subsets encompassing these T-cell populations. These effects of the PGE2/Wnt/β-catenin axis may have significant implications for harnessing immunity in the context of UCBT, where impaired immune reconstitution is associated with late memory T-cell skewing.
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Li
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Kim
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Nellore
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Patsoukis
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
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Petkova
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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McDonough
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Politikos
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Nikiforow
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Soiffer
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Antin
Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
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Ballen
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Cutler
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Ritz
Department of Medicine, Division of Hematology/Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Boussiotis