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Journal of Neuroimmune Pharmacology

, Volume 9, Issue 4, pp 522–532 | Cite as

Epigenetic Modification of the FoxP3 TSDR in HAM/TSP Decreases the Functional Suppression of Tregs

  • Monique R. Anderson
  • Yoshimi Enose-Akahata
  • Raya Massoud
  • Nyater Ngouth
  • Yuetsu Tanaka
  • Unsong Oh
  • Steven JacobsonEmail author
ORIGINAL ARTICLE

Abstract

HTLV-1 is a human retrovirus that is associated with the neuroinflammatory disorder HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). In these patients, HTLV-1 is primarily found in the CD4+CD25+ T cell subset (Regulatory T cells:Tregs), which is responsible for peripheral immune tolerance and is known to be dysfunctional in HAM/TSP. Recent evidence suggests that FoxP3 expression and function is determined epigenetically through DNA demethylation in the Treg-specific demethylated region (TSDR). We analyzed the methylation of the TSDR in PBMCs, CD4+ T cells, and CD4+CD25+ T cells from normal healthy donors (NDs) and HAM/TSP patients. We demonstrated that there is decreased demethylation in analyzed PBMCs and CD4+CD25+ T cells from HAM/TSP patients as compared to NDs. Furthermore, decreased TSDR demethylation was associated with decreased functional suppression by Tregs. Additionally, increased HTLV-1 Tax expression in HAM/TSP PBMC culture correlated with a concomitant decline in FoxP3 TSDR demethylation. Overall, we suggest that HTLV-1 infection decreases Treg functional suppressive capacity in HAM/TSP through modification of FoxP3 TSDR demethylation and that dysregulated Treg function may contribute to HAM/TSP disease pathogenesis.

Keywords

Regulatory T cells HTLV-1 Treg specific demethylation region (TSDR) Epigenetic regulation Suppressive capacity Demethylation 

Notes

Acknowledgments

Special thanks to Mr. Matt McCormick for his contributions to the demethylation protocols developed for this study.

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2014

Authors and Affiliations

  • Monique R. Anderson
    • 1
    • 2
    • 3
  • Yoshimi Enose-Akahata
    • 1
  • Raya Massoud
    • 1
  • Nyater Ngouth
    • 1
  • Yuetsu Tanaka
    • 4
  • Unsong Oh
    • 5
  • Steven Jacobson
    • 1
    Email author
  1. 1.Neuroimmunology Branch, Viral Immunological SectionNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA
  2. 2.Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Howard Hughes Medical InstituteChevy ChaseUSA
  3. 3.Department of PathologyUniversity of Virginia School of Medicine, Molecular and Cellular Basis of Disease Graduate ProgramCharlottesvilleUSA
  4. 4.Department of Immunology, Graduate School of MedicineUniversity of the RyukyusNishihara-choJapan
  5. 5.Department of NeurologyVirginia Commonwealth UniversityRichmondUSA

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