Stabilization of Foxp3 by Targeting JAK2 Enhances Efficacy of CD8 Induced Regulatory T Cells in the Prevention of Graft-versus-Host Disease

The Journal of Immunology : Official Journal of the American Association of Immunologists
Supinya IamsawatXue-Zhong Yu

Abstract

CD8+ induced regulatory T cells (iTregs) have been identified to suppress alloreactive immune responses and expressed regulatory T cell (Treg) ontological markers as similar as CD4+ iTregs. However, adoptive transfer of CD8+ iTreg-based therapy is hampered by the instability of Treg specific-transcription factor, Foxp3. As CD8+ iTregs were previously demonstrated to possess superior tumor-killing ability to CD4+ iTregs, adoptive transfer of stabilized CD8+ iTregs would be a potential therapy to prevent tumor relapse during graft-versus-leukemia disease (GVHD) treatment. In the current study, we generated alloantigen reactive CD8+ iTregs from JAK2-/- T cells and adoptively transferred them to MHC-mismatched and haploidentical murine models of allogeneic bone marrow transplantation. JAK2-/- CD8+ iTregs not only attenuated GVHD but also preserved graft-versus-leukemia effect. Mechanistic analysis revealed that JAK2-/- CD8+ iTregs upregulated natural Treg marker (neuropilin-1), and augmented DNA demethylation of CNS2 region within Foxp3 gene. These properties licensed JAK2-/- CD8+ iTregs to retain high Foxp3 expression resulting in less conversion to type 1 CTLs; as a result, JAK2-/- CD8+ iTregs were able to maintain their suppress...Continue Reading

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Citations

Aug 17, 2019·British Journal of Haematology·Shlomo Elias, Alexander Y Rudensky
Oct 17, 2019·Frontiers in Immunology·Peter D Bittner-EddyMassimo Costalonga
Mar 25, 2019·Frontiers in Immunology·Govindarajan Thangavelu, Bruce R Blazar
Jan 25, 2021·International Immunopharmacology·Qianqian YuWei Wei
Jan 28, 2021·European Journal of Immunology·Veronika NiederlovaOndrej Stepanek
Mar 30, 2021·Journal of Inflammation Research·Zeev Elkoshi

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