Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity

Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2013; DOI: 10.1084/jem.20121611
Source: PubMed


Reliable biomarkers corresponding to disease progression or therapeutic responsiveness in multiple sclerosis (MS) have not been yet identified. We previously reported that low expression of the antiproliferative gene TOB1 in CD4(+) T cells of individuals presenting with an initial central nervous system (CNS) demyelinating event (a clinically isolated syndrome), correlated with high risk for progression to MS. We report that experimental autoimmune encephalomyelitis (EAE) in Tob1(-/-) mice was associated with augmented CNS inflammation, increased infiltrating CD4(+) and CD8(+) T cell counts, and increased myelin-reactive Th1 and Th17 cells, with reduced numbers of regulatory T cells. Reconstitution of Rag1(-/-) mice with Tob1(-/-) CD4(+) T cells recapitulated the aggressive EAE phenotype observed in Tob1(-/-) mice. Furthermore, severe spontaneous EAE was observed when Tob1(-/-) mice were crossed to myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic (2D2) mice. Collectively, our results reveal a critical role for Tob1 in adaptive T cell immune responses that drive development of EAE, thus providing support for the development of Tob1 as a biomarker for demyelinating disease activity.

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Available from: Sergio E Baranzini
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    • "In conclusion, our data are consistent with recently published experiments by Macian’s group in a tumor-induced anergy system [11] in showing that intrinsic negative regulation of T-cell proliferation is a prominent role for Nfatc2, and its duality as a master controller of Tregs is less evident in the B6 background. These activities seem to be distinct from and non-redundant with the role of Tob1, whose intrinsic negative regulatory function extends to Tregs, and which appears to have a prominent function in restraining autoreactivity [21], [22]. Further studies are needed to assess the potential for selective modulation of Nfatc2, Tob1, or both as part of therapeutic strategies seeking to alter T cell responses in patients with autoimmune diseases and cancer. "
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