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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5418.
HTLV-I, Tax: fox hunting still allowedINSTITUT PASTEUR, INSERM
A defect in TGF-β signaling is observed in HTLV-I–infected cells obtained from HAM/TSP patients. This is associated with low levels of Foxp3 expression and with disruption of both T regulatory and T effectors functions. Disruption of TGF-β signaling is therefore likely to participate in HAM/TSP pathogenesis.
Although it is known that Tax proviral load and a dysregulated immune response play major roles in disease progression, HAM/TSP pathogenesis is still poorly understood. To explain the role of HTLV-I in the progression of HAM/TSP, 3 mechanisms have been proposed1: an antiviral attack mediated by cytotoxic T lymphocytes,2 an autoimmune response,3 or bystander damage due to cytokines such as TNF- CD4+/CD25+ T cells expressing the forkhead transcription factor Foxp3 are defined as regulatory T cells (Tregs). These cells play a key role in the maintenance of immune system homeostasis. As shown by 2 recent reports, Tregs from HAM/TSP patients express low levels of Foxp3 and have impaired suppressor functions,5,6 while another apparently conflicting set of findings shows a strong negative correlation between the frequency of circulating CD4+ Foxp3+ Tax– Tregs and the rate of cytotoxic T lymphocyte–mediated lysis of autologous HTLV-I–infected cells.7 Prior to the findings reported by Grant and colleagues in this issue of Blood, the mechanism leading to defective Treg function was not clear. Because TGF-β signaling is involved in Foxp3 expression and Treg suppressor function, Grant and colleagues investigated whether TGF-β signaling was affected in CD4+ cells isolated from HAM/TSP patients. They first demonstrated that the levels of TGF-β receptor II (TGF-βRII) were low in these cells, and that an inverse correlation between TGF-βRII expression and Tax proviral load could be measured. Interestingly, the capability of TGF-β to induce Foxp3 expression in CD+/CD25– Foxp3– cells isolated from HAM/TSP patients was also weakened. Then, they showed that knocking out the expression of Smad4, a TGF-inducible gene, caused a massive reduction in Foxp3 levels, confirming that integrity of the TGF-β signaling pathway must be maintained for normal Foxp3 expression. However, whether the Foxp3 promoter contains Smad4 binding sites or not, and how exactly TGF-β signaling is impaired by HTLV-I, remains to be determined. Is the mechanism similar to that previously described for HTLV-I adult T-cell leukemia/lymphoma cells?8 Finally, the authors established that CD4+/CD25+ T cells isolated from a series of HAM/TSP patients failed to suppress the proliferation of CD4+/CD25– T cells isolated from the same individuals. This latter population was also resistant to suppression mediated by Treg cells obtained from normal donors. Altogether, these results undoubtedly show that because of a defect in TGF-β signaling, Foxp3 expression is decreased, and both Treg and effector T-cell functions are impaired in HAM/TSP patients. It is tempting to speculate that these deficiencies play key roles in the progression of the disease.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
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