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 Blood, 15 June 2008, Vol. 111, No. 12, pp. 5601-5609.
Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-11-123430.

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IMMUNOBIOLOGY

Dysregulation of TGF-β signaling and regulatory and effector T-cell function in virus-induced neuroinflammatory disease

Christian Grant1, Unsong Oh1, Karen Yao1, Yoshihisa Yamano2, and Steven Jacobson1

1 Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD; and 2 Kagoshima City Hospital, Kagoshima, Japan

We previously demonstrated that CD4+CD25+ T regulatory cells (Tregs), important for the maintenance of immune tolerance and prevention of autoimmune disease, from patients with human T lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) exhibit reduced Foxp3 expression and Treg suppressor function compared with healthy donors. Since TGF-β signaling has been previously reported to be critical for both Foxp3 expression and Treg function, we examined whether this signaling pathway was dysregulated in patients with HAM/TSP. Levels of TGF-β receptor II (TGF-βRII) as well as Smad7 (a TGF-β–inducible gene) were significantly reduced in CD4+ T cells in patients with HAM/TSP compared with healthy donors, and the expression of TGF-βRII inversely correlated with the HTLV-I tax proviral load. Importantly, both CD4+CD25+ and CD4+CD25– T cells from HAM/TSP patients exhibited reduced TGF-βRII expression compared with healthy donors, which was associated with functional deficits in vitro, including a block in TGF-β–inducible Foxp3 expression that inversely correlated with the HTLV-I tax proviral load, loss of Treg suppressor function, and escape of effector T cells from Treg-mediated control. This evidence suggests that a virus-induced breakdown of immune tolerance affecting both regulatory and effector T cells contributes to the pathogenesis of HAM/TSP.


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Related Article in Blood Online:

HTLV-I, Tax: fox hunting still allowed
Renaud Mahieux
Blood 2008 111: 5418. [Full Text] [PDF]





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