Bonaguro, Lorenzo: Creld1 controls T cell homeostasis in mouse and human. - Bonn, 2020. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-58859
@phdthesis{handle:20.500.11811/8437,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-58859,
author = {{Lorenzo Bonaguro}},
title = {Creld1 controls T cell homeostasis in mouse and human},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2020,
month = jul,

note = {Cysteine-rich with EGF-like domains 1 (Creld1) was recently found to be fundamental for the VEGF-mediated activation of NFATc1 during heart development. Creld1 complete KO in mice is lethal due to developmental problems during heart formation. Due to the broad expression of Creld1 across almost all cell types and tissues, I wanted to identify additional roles this protein might have in other cellular contexts. In this thesis, I could show how Creld1 functions as a modulator in both the canonical and non-canonical Wnt signalling pathway using an overexpression cell culture system and a conditional KO mouse model for Creld1 in T lymphocytes (CD4Cre; Creld1flox/flox). Furthermore, I could show how Creld1 acts as a plasma membrane protein through its cytosol-facing C-terminus, physically interacting with Wnt signalling components, upstream of β-Catenin and NFAT activation but downstream of Wnt binding to the Frizzled receptor. These data were confirmed in Creld1 KO CD4+ T cells where a general downregulation of both canonical and non-canonical Wnt signalling was observed in homeostasis. Both, ex vivo and in vivo, Creld1 promote viability in CD4+ T cells showing, in a conditional KO model, a dramatic increase of apoptotic cell death ex vivo and a marked reduction of total cell number in one-year-old animals in vivo. Furthermore, Creld1 depletion in CD4+ T cells also affects main T cell effector functions showing an imbalanced activation kinetic and a differential proliferative capacity in accordance with current models of Wnt signalling as modulators of CD4+ T cell homeostasis. Transcriptomic analysis of Creld1-deficient CD4+ T cells further confirmed the cell-intrinsic defect in cell homeostasis and Wnt signalling activation and allowed the definition of a transcriptional footprint of Creld1 in T cells. This transcriptional signature was then shown to be conserved in human CD4+ T cells when individual with low CRELD1 expression were compared to high expressing ones showing a conserved role of CRELD1 in human CD4+ T cells. CRELD1low transcriptional analysis also recapitulated the main phenotype found in the murine mouse model with a general down-regulation of Wnt signalling hallmark genes and an obvious apoptotic signature. The CRELD1-dependent transcriptional regulation was then shown to be conserved also in other immune cells and even visible in total PBMCs. Interestingly, I correlated changes in CRELD1 expression to the process of immunosenescence in accordance with the phenotype of one-year-old mice. Taken together, this work suggests Creld1 as an important regulator of the Wnt signalling pathway in both mouse and human preventing the process of senescence of immune cells and highlighting this protein as a possible target in the treatment of age-related diseases.},
url = {https://hdl.handle.net/20.500.11811/8437}
}

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