Epigenetic modification of the FoxP3 TSDR in HAM/TSP decreases the functional suppression of Tregs.
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.
Neuroimmunology Branch, Viral Immunological Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive Rm 5C103, Bethesda, MD, 20892, USA.
Monique R
MR
Anderson
Yoshimi
Y
Enose-Akahata
Raya
R
Massoud
Nyater
N
Ngouth
Yuetsu
Y
Tanaka
Unsong
U
Oh
Steven
S
Jacobson
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016356:Gene Products, tax / Q000096:biosynthesis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000235:genetics* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016356:Gene Products, tax