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.

Gene Expression Profiling in Preterm Infants: New Aspects of Bronchopulmonary Dysplasia Development

“…The production of cytokines is essentially controlled by transcription factors [43]. In our study, transcription factors and related pathways were under-expressed in children with BPD.…”

Prediction of combination therapies based on topological modeling of the immune signaling network in Multiple Sclerosis

“…Moreover, STAT3 has been confirmed as susceptibility gene for the disease (35) , and its activation is impaired in response to IL-10 in MS patients (36) , suggesting a defective response of regulatory Tr1 cells. Regarding the interactions that were decreased in MS patients compared to controls, PBMCs from patients with MS showed lowered inhibition of STAT5 by LCK suggesting impairment of the regulation of T/B-cell signaling and IL-2 trophic effects (37) or cytotoxicity (38) , as well as the regulation of the ubiquitination system modulated by CBL-B (39) . LCK is modulated by EVI5, and influences STAT5 in our analysis, both being susceptibility genes for MS (35) .…”

GATA3 controls mitochondrial biogenesis in primary human CD4+T cells during DNA damage

“…T-bet, which is also known to be crucial for long-term memory in CD8 + T cells (Intlekofer et al, 2005;Juedes, Glimcher, Szabo, von Herrath, & Sullivan, 2003) and maturation of NK cells (Townsend et al, 2004). More recently; STAT5, which has traditionally been associated with cytokine signalling and JAK kinases (Beyer et al, 2011), has now also been identified as a central regulator of naïve CD4 + T cell metabolism (Jones et al, 2019). Furthermore, although the GATA proteins have restricted expression patterns to some extent their functions can be interchangeable.…”