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

• Published in: Journal of neuroimmune pharmacology Vol. 9; no. 4; pp. 522 - 532
• Main Authors: Anderson, Monique R., Enose-Akahata, Yoshimi, Massoud, Raya, Ngouth, Nyater, Tanaka, Yuetsu, Oh, Unsong, Jacobson, Steven
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-09-2014; Springer Nature B.V
• Subjects: Adult; Aged; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; CD4-Positive T-Lymphocytes - metabolism; Cell Biology; Cells, Cultured; DNA Methylation; Epigenesis, Genetic; Female; Forkhead Transcription Factors - metabolism; Gene Products, tax - biosynthesis; Humans; Immunology; Leukocytes, Mononuclear - metabolism; Lymphocytes; Male; Middle Aged; Neurosciences; Original Article; Paraparesis, Tropical Spastic - genetics; Paraparesis, Tropical Spastic - metabolism; Pharmacology/Toxicology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Virology; Demethylation; HTLV-1; Epigenetic regulation; Regulatory T cells; Suppressive capacity; Treg specific demethylation region (TSDR)
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-014-9547-z

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.