Stabilization of Foxp3 by Targeting JAK2 Enhances Efficacy of CD8 Induced Regulatory T Cells in the Prevention of Graft-versus-Host Disease. J Immunol 2018 Nov 01;201(9):2812-2823
Date
09/23/2018Pubmed ID
30242073Pubmed Central ID
PMC6200641DOI
10.4049/jimmunol.1800793Scopus ID
2-s2.0-85055172850 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Iamsawat S, Daenthanasanmak A, Voss JH, Nguyen H, Bastian D, Liu C, Yu XZAuthor
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Forkhead Transcription Factors
Graft vs Leukemia Effect
Janus Kinase 2
Mice
T-Lymphocytes, Regulatory
