| First Author | Iamsawat S | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 9 | Pages | 2812-2823 |
| PubMed ID | 30242073 | Mgi Jnum | J:267000 |
| Mgi Id | MGI:6257946 | Doi | 10.4049/jimmunol.1800793 |
| Citation | Iamsawat S, et al. (2018) Stabilization of Foxp3 by Targeting JAK2 Enhances Efficacy of CD8 Induced Regulatory T Cells in the Prevention of Graft-versus-Host Disease. J Immunol 201(9):2812-2823 |
| abstractText | 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. |
