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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.

SUBMITTER: Yamano Y

PROVIDER: S-EPMC1087174 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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

Yamano Yoshihisa Y Takenouchi Norihiro N Li Hong-Chuan HC Tomaru Utano U Yao Karen K Grant Christian W CW Maric Dragan A DA Jacobson Steven S

The Journal of clinical investigation 20050501 5

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 ...[more]

PMID: 15864353

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Project description:BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs) are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127(-ve)FoxP3+ Tregs in HBV-related HCC as compared to non-HBV-HCC.Patients and methodsWhole blood immunophenotyping was analyzed by multicolor flow cytometry in patients with HBV-related HCC (HBV-HCC, n = 17), non-HBV-HCC (n = 22; NASH = 16, alcohol-related = 6), and chronic hepatitis B infection (CHBV; n = 10). Tregs functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127(low) Tregs. Levels of serum alpha-fetoprotein (AFP), expression of FoxP3, IL-10, PD1, TGF-β, and Notch in Tregs, and liver explants were analyzed by flow cytometry, immunohistochemistry, and quantitative RT-PCR.ResultsCD4+CD25+(hi) and Foxp3 expression in CD4+CD25+(hi)CD127(low) was significantly increased (P = 0.04, P = 0.007) in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10 and TGF-β secreting CD4 + CD25 + (hi)Tregs. The PD1 expression in CD4 + CD25+(hi) was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2-727940) than non-HBVHCC (median 13.5, range 2-18,900). In HBVHCC, patients with high AFP (range; 3982-727940 ng/ml) showed positive correlation with Foxp3 expression in CD4+CD25+(hi) CD127(low) (r = 0.857, P = 0.014). Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+(hi) CD127(low) (r = -0.78, P = 0.04). However, AFP levels in non-HBVHCC showed negative correlation with (R = -0.67, P = 0.005) with CD4+CD25+(hi) Tregs.ConclusionOur results demonstrate that CD4+ CD25+(hi) Tregs from HBVHCC patients have decreased expression of PD1, resulting in higher IL-10 and TGF-β secretion. Increased suppressive ability of Tregs in HBV-related HCC confers increased anti-tumor suppressive response than in non-HBV-HCC. Modulation of Tregs and PD1 may serve as useful therapeutic targets.

Dataset Information

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

Publications

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

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