Submitted November 14, 2007
Accepted February 29, 2008
Dysregulation of TGF-
signaling and regulatory and effector T cell function in virus-induced neuroinflammatory disease
Christian Grant, Unsong Oh, Karen Yao, Yoshihisa Yamano, and Steven Jacobson*
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
Department of Medicine, Kagoshime City Hospital, Kagoshima, Japan
* Corresponding author; email: jacobsons{at}ninds.nih.gov.
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 to normal donors. Since TGF-
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- receptor II (TGF-RII) as well as Smad7 (a TGF--inducible gene) were significantly reduced in CD4+ T cells in patients with HAM/TSP compared to normal donors, and the expression of TGF-RII 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-RII expression compared to normal donors, which was associated with functional deficits in vitro, including a block in TGF--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.
