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

Supinya Iamsawat1, Anusara Daenthanasanmak1, Jessica Heinrichs Voss1, Hung Nguyen1, David Bastian1, Chen Liu2, Xue-Zhong Yu3,4
1Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425.
2Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901; and.
3Department of Medicine, Medical University of South Carolina, Charleston, SC 29425
4Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; [email protected].

Tóm tắt

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 suppressive and cytolytic function. Thus, our findings provide a strong rationale and means to stabilize CD8+ iTregs by targeting JAK2, and the stabilized CD8+ iTregs exhibit therapeutic potential for alleviating GVHD and preserving the graft-versus-leukemia effect.

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