Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I–associated neuroimmunological disease
Yoshihisa Yamano, … , Dragan A. Maric, Steven Jacobson
Yoshihisa Yamano, … , Dragan A. Maric, Steven Jacobson
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1361-1368. https://doi.org/10.1172/JCI23913.
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Article Immunology

Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I–associated neuroimmunological disease

Abstract

CD4+CD25+ Tregs are important in the maintenance of immunological self tolerance and in the prevention of autoimmune diseases. As the CD4+CD25+ T cell population in patients with human T cell lymphotropic virus type I–associated (HTLV-I–associated) myelopathy/tropical spastic paraparesis (HAM/TSP) has been shown to be a major reservoir for this virus, it was of interest to determine whether the frequency and function of CD4+CD25+ Tregs in HAM/TSP patients might be affected. In these cells, both mRNA and protein expression of the forkhead transcription factor Foxp3, a specific marker of Tregs, were lower than those in CD4+CD25+ T cells from healthy individuals. The virus-encoded transactivating HTLV-I tax gene was demonstrated to have a direct inhibitory effect on Foxp3 expression and function of CD4+CD25+ T cells. This is the first report to our knowledge demonstrating the role of a specific viral gene product (HTLV-I Tax) on the expression of genes associated with Tregs (in particular, foxp3) resulting in inhibition of Treg function. These results suggest that direct human retroviral infection of CD4+CD25+ T cells may be associated with the pathogenesis of HTLV-I–associated neurologic disease.

Authors

Yoshihisa Yamano, Norihiro Takenouchi, Hong-Chuan Li, Utano Tomaru, Karen Yao, Christian W. Grant, Dragan A. Maric, Steven Jacobson

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Figure 1

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Decreased Foxp3 expression in CD4+CD25+ T cells from HAM/TSP patients. (...
Decreased Foxp3 expression in CD4+CD25+ T cells from HAM/TSP patients. (A) Quantitative expression of foxp3 mRNA was determined by real-time RT-PCR. The level of foxp3 mRNA expression was calculated as the relative quantity of foxp3 mRNA expression divided by the relative quantity of endogenous control HPRT mRNA expression, as described in Methods. The data represent isolated cell subsets (CD4+CD25+ or CD4+CD25–) from 13 uninfected HDs and 13 HAM/TSP patients (HAM). Foxp3 mRNA expression was significantly reduced in the CD4+CD25+ T cell subset from HDs compared with that from HAM/TSP patients. (B) A representative histogram of intracellular expression of Foxp3 protein showing results from flow cytometric analysis of PBMC samples from HAM/TSP patients and HDs. Foxp3 protein expression was detected in the CD4+CD25+ T cell subset from HDs but not in CD4+CD25– or in total CD4– T cell subsets. In contrast, the number of Foxp3-positive cells in CD4+CD25+ T cells from HAM/TSP patients was clearly reduced. (C) Data represent averaged percentage of Foxp3-positive cells in each T cell subset. The percentage (mean ± SD) of Foxp3-positive cells in CD4+CD25+ T cells of 8 HAM/TSP patients (3.09% ± 1.04%) was significantly lower than that of 8 HDs (25.9% ± 8.23%; P = 0.0014). No difference in the protein expression levels of Foxp3 was observed in CD4+CD25– or CD4– cells between HAM/TSP patients and HDs.