HTLV-I, Tax: fox hunting still allowed.

HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in a subset of human T lymphotropic virus type I (HTLV-I)–infected individuals.1 Its evolution is chronic and progressive, without remission.2 Recently, a study using a histone deacetylase inhibitor reported, for the first time, a spectacular decline in the HTLV-I proviral load in a series of HAM/TSP patients.3 Unfortunately, clinical benefits were limited. 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.4 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 TGFsignaling is involved in Foxp3 expression and Treg suppressor function, Grant and colleagues investigated whether TGFsignaling was affected in CD4 cells isolated from HAM/TSP patients. They first demonstrated that the levels of TGFreceptor II (TGFRII) were low in these cells, and that an inverse correlation between TGFRII expression and Tax proviral load could be measured. Interestingly, the capability of TGFto 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 TGFsignaling pathway must be maintained for normal Foxp3 expression. However, whether the Foxp3 promoter contains Smad4 binding sites or not, and how exactly TGFsignaling 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 TGFsignaling, 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. Conflict-of-interest disclosure: The author declares no competing financial interests. ■