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

Schulze-Topphoff, Ulf; Casazza, Simona; Varrin‐Doyer, Michel; Pekarek, Kara; Sobel, Raymond A.; Hauser, Stephen L.; Oksenberg, Jorge R.; Zamvil, Scott S.; Baranzini, Sergio E.

doi:10.1084/jem.20121611

Cited by 45 publications

(50 citation statements)

References 30 publications

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“…Mononuclear cells (MNCs) were isolated from the spleens of Tob1 −/− mice and Tob1 +/+ littermates at baseline and at day 15 after EAE induction (15 dpi), corresponding to the peak of the disease11. Total RNA was purified from each cell sample and subjected to microarray hybridization as described in the Material and Methods section.…”

Section: Resultsmentioning

confidence: 99%

Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Didonna

Cekanaviciute

Oksenberg

et al. 2016

Sci Rep

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by focal lymphocytic infiltration, demyelination and neurodegeneration. Despite the recent advances in understanding MS molecular basis, no reliable biomarkers have been identified yet to monitor disease progression. Our group has previously reported that low levels of TOB1 in CD4+ T cells are strongly associated with a higher risk of MS conversion in individuals experiencing an initial demyelinating event. Consistently, Tob1 ablation in mice exacerbates the clinical phenotype of the MS model experimental autoimmune encephalomyelitis (EAE). To shed light on Tob1 molecular functions in the immune system, we have conducted the first cell-based transcriptomic analysis in Tob1−/− and wildtype mice upon EAE. Next-generation sequencing was employed to characterize the changes in gene expression in T and B cells at pre- and post-symptomatic EAE stages. Remarkably, we found only modest overlap among the different genetic signatures, suggesting that Tob1 may control distinct genetic programs in the different cytotypes. This hypothesis was corroborated by gene ontology and global interactome analyses, which highlighted specific cellular pathways in each cellular subset before and after EAE induction. In summary, our work pinpoints a multifaceted activity of Tob1 in both homeostasis and disease progression.

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Section: Resultsmentioning

confidence: 99%

Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Didonna

Cekanaviciute

Oksenberg

et al. 2016

Sci Rep

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“…Recently, IL4I1 has been shown to maintain the expression of Tob1, an antiproliferative protein, which is necessary to limit CD4 + T cell proliferation (Santarlasci et al , 2014). Furthermore, Tob1 deficiency in mice with EAE results in enhanced CNS inflammation (Schulze-Topphoff et al , 2013). In fact, individuals presenting with an initial demyelination episode who also display low Tob1 expression are more likely to progress to multiple sclerosis from clinically isolated syndrome than those with high Tob1 level (Corvol et al , 2008).…”

Section: Discussionmentioning

confidence: 99%

IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

Psachoulia

Chamberlain

Heo

et al. 2016

Brain

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See Pluchino and Peruzzotti-Jametti (doi:) for a scientific commentary on this article.Macrophages have a critical role in remyelination. Psachoulia et al. show that IL4I1, a macrophage-secreted enzyme, promotes CNS remyelination by modulating T cell driven inflammation after focal demyelination in mice. Injection of recombinant IL4I1 protein reverses disease progression in a mouse model of multiple sclerosis, resulting in recovery from hindlimb paralysis.

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“…Very recently, by investigating the role of Tob1 in EAE, it was found that immunization of Tob1 −/− mice with myelin oligodendrocyte glycoprotein peptide 35-55 resulted in an earlier disease onset, an increase in the maximum clinical score, and a greater and sustained disease severity in comparison with wildtype mice [23]. The exacerbated EAE phenotype in Tob1 −/− mice associated with augmented CNS inflammation, increased infiltration of CD4 + and CD8 + T cells, and higher numbers of myelinreactive Th1 and Th17 cells, whereas the numbers of regulatory T cells were reduced [23]. Thus, our data provide an explanation for the reason why Tob1 can play an important regulatory role in the development and/or severity of this important disorder of the CNS and perhaps of other Th17-related chronic inflammatory processes in both humans and mice.…”

Section: High Tob1 Expression In Th17 Cells Is Dependent Upon Il4i1 Umentioning

confidence: 99%

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

et al. 2013

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Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets.We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle. Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Annunziato e-mail: francesco.annunziato@unifi.it * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 654-661 HIGHLIGHTS 655 IntroductionActivated CD4 + T cells can be subdivided into lineages on the basis of their cytokine production, their specific transcription factor expression and their immunological function: T helper type 1 (Th1) cells express the transcription factor T-box expressed in T cells, secrete IFN-γ, and protect the host against intracellular infections; Th2 cells express the transcription factor GATA-3, secrete IL-4, IL-5, and IL-13, and mediate host defense against helminths; Th17 cells selectively produce IL-17A, express the transcription factor retinoic acid receptor (RAR) related orphan receptor γt, and are critical for the host's defense against extracellular pathogens [1][2][3][4]. Moreover, a subset of human IL-17A-producing CD4 + T cells was found to also produce IFN-γ (Th17/Th1) and both Th17 and Th17/Th1 cells exhibit plasticity toward the Th1 profile when cultured in the presence of . Similar findings were also reported in some murine models [5][6][7] suggesting that both human and murine Th17 cells probably represent a transient phenotype [8]. We have also shown that virtually all human memory Th17 cells are contained within the CD161 + fraction of both circulating and tissue-infiltrating CD4 + T cells, and originate from CD161 + precursors present in umbilical cord blood and newborn thymus [9]. In humans, Th1 cells that derive from the shif...

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

Abstract: Loss of antiproliferative gene TOB1 results in more severe EAE driven by augmented pathogenic T cell responses.

Cited by 45 publications

References 30 publications

Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

IL‐4‐induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

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