HTLV-I, Tax: fox hunting still allowed

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.

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-α.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 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.