@article{SchneiderSchauliesMuellerAvotaetal.2014,
  author    = {Schneider-Schaulies, Sibylle and Mueller, Nora and Avota, Elita and Collenburg, Lena and Grassm{\´e}, Heike},
  title     = {Neutral Sphingomyelinase in Physiological and Measles Virus Induced T Cell Suppression},
  doi       = {10.1371/journal.ppat.1004574},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111038},
  year      = {2014},
  abstract  = {T cell paralysis is a main feature of measles virus (MV) induced immunosuppression. MV contact mediated activation of sphingomyelinases was found to contribute to MV interference with T cell actin reorganization. The role of these enzymes in MV-induced inhibition of T cell activation remained equally undefined as their general role in regulating immune synapse (IS) activity which relies on spatiotemporal membrane patterning. Our study for the first time reveals that transient activation of the neutral sphingomyelinase 2 (NSM2) occurs in physiological co-stimulation of primary T cells where ceramide accumulation is confined to the lamellum (where also NSM2 can be detected) and excluded from IS areas of high actin turnover. Genetic ablation of the enzyme is associated with T cell hyper-responsiveness as revealed by actin dynamics, tyrosine phosphorylation, Ca2+-mobilization and expansion indicating that NSM2 acts to suppress overshooting T cell responses. In line with its suppressive activity, exaggerated, prolonged NSM2 activation as occurring in co-stimulated T cells following MV exposure was associated with aberrant compartmentalization of ceramides, loss of spreading responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression.},
  language  = {en}
}
@article{KimGrimmigGrimmetal.2013,
  author    = {Kim, Mia and Grimmig, Tanja and Grimm, Martin and Lazariotou, Maria and Meier, Eva and Rosenwald, Andreas and Tsaur, Igor and Blaheta, Roman and Heemann, Uwe and Germer, Christoph-Thomas and Waaga-Gasser, Ana Maria and Gasser, Martin},
  title     = {Expression of Foxp3 in Colorectal Cancer but Not in Treg Cells Correlates with Disease Progression in Patients with Colorectal Cancer},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0053630},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130340},
  pages     = {e53630},
  year      = {2013},
  abstract  = {Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.},
  language  = {en}
}
@article{RiedelMofoloAvotaetal.2013,
  author    = {Riedel, Alice and Mofolo, Boitumelo and Avota, Elita and Schneider-Schaulies, Sibylle and Meintjes, Ayton and Mulder, Nicola and Kneitz, Susanne},
  title     = {Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0050695},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130335},
  pages     = {e50695},
  year      = {2013},
  abstract  = {Background Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results Applying our algorithm to the data, 9\% of the genes were assigned as AS, while only 3\% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.},
  language  = {en}
}