title: Integrating signals from the T-cell receptor and the interleukin-2 receptor.
abstract: T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Beyer
authors.forename: Mandy
authors.initials: M
authors.lastname: Busse
authors.forename: Kroum
authors.initials: K
authors.lastname: Hristov
authors.forename: Slavyana
authors.initials: S
authors.lastname: Gurbiel
authors.forename: Michal
authors.initials: M
authors.lastname: Smida
authors.forename: Utz-Uwe
authors.initials: UU
authors.lastname: Haus
authors.forename: Kathrin
authors.initials: K
authors.lastname: Ballerstein
authors.forename: Frank
authors.initials: F
authors.lastname: Pfeuffer
authors.forename: Robert
authors.initials: R
authors.lastname: Weismantel
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lindquist
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D050791:STAT Transcription Factors; D019061:src-Family Kinases