Article

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: 13.91). 06/2013; DOI: 10.1084/jem.20121611
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Sergio E Baranzini, Jul 10, 2015
0 Followers
 · 
110 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which destruction of myelin and nerve axons has been shown to be mediated by immune mechanisms. Although the focus of research has been traditionally on T cells as key mediators of the immunopathology, more recent efforts at understanding this complex disorder have been directed increasingly at other cellular and humoral elements of the immune response. This review is a reappraisal of the crucial role of T cells, in particular the CD4+ helper T-cell subset, in multiple sclerosis. Recent evidence is discussed underlining the predominant contribution of T-cell-associated genes to the genome-wide association study results of multiple sclerosis susceptibility, the loss of T-cell quiescence in the conversion from clinically isolated syndrome to clinically definite multiple sclerosis, and the fact that T cells represent the main target of effective immunomodulatory and immunosuppressive treatments in multiple sclerosis.
    01/2014; 37(2):34-40. DOI:10.4103/2319-4170.128746
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In MS, we've advanced from a state in which essentially nothing could be done for our patients to a new challenge: how to select the best medication for an individual patient from among nine FDA-approved choices, with more expected soon to launch. Clinical progress has occurred in part because MS is a more tractable problem than, for example, a classical neurodegenerative disease. In MS progress was achieved almost exclusively by developing immunotherapies that kill, attenuate, or disable overactive autoreactive lymphocytes. An unsolved challenge in MS is how to protect against late neurodegeneration, the major cause of chronic disability in this disease. One noteworthy feature of the MS success story is that, despite progress, we still do not have a coherent model of pathogenesis. We do not know the primary trigger or triggers, the specificity of the culprit pathogenic immune cells, or the mechanism underlying progressive disability in longstanding disease. MS also remains one of the most compelling mysteries in modern medicine. Why has it increased in frequency over the past century and why may have this increase occurred mostly in women? What is the cause of progression? And why in 15% of patients does the disease manifest only as gradual, primary progression [primary progressive MS (PPMS)], with focal areas of inflammation and gliosis visible on MRI presenting as a gradual accumulation of disability rather than as clinical relapses? This selective overview will highlight recent progress, and outline a few areas that are particularly ripe for meaningful advances in the near future. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 08/2013; 74(3). DOI:10.1002/ana.24009 · 11.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion. The limited expansion of human Th17 cells is related to the retinoic acid orphan (ROR)C-dependent up-regulation of the interleukin (IL)-4 induced gene 1 (IL4I1), which encodes for a l-phenylalanine oxidase, that has been shown to down-regulate CD3ζ expression in T cells. This results in abnormalities of the molecular pathway which is responsible for the impairment of IL-2 production and therefore for the lack of cell proliferation in response to T-cell receptor (TCR) signalling. IL4I1 up-regulation also associates with the increased expression of Tob1, a member of the Tob/BTG anti-proliferative protein family, which is involved in cell cycle arrest. A second reason for the rarity of human Th17 cells in the inflammatory sites is their rapid shifting into the Th1 phenotype, which is mainly related to the activity of IL-12 and TNF-α. We have named these Th17-derived Th1 cells as non-classic because they differ from classic Th1 cells for the expression of molecules specific for Th17 cells, such as RORC, CD161, CCR6, IL4I1, and IL-17 receptor E. This distinction may be important for defining the respective pathogenic role of Th17, non-classic Th1 and classic Th1 cells in many human inflammatory disorders.
    Seminars in Immunology 11/2013; 25(4). DOI:10.1016/j.smim.2013.10.011 · 6.12 Impact Factor
Show more