The guanine-nucleotide exchange factor CalDAG GEFI fine-tunes functional properties of regulatory T cells
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1886.2017.00007.pdf
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Author(s)
Niemz, Jana
Kliche, Stefanie
Pils, Marina C.
Morrison, Eliot
Manns, Annika
Freund, Christian
Galla, Melanie
Jänsch, Lothar
Huehn, Jochen
Crittenden, Jill R
Date Issued
May 2017
Journal
European Journal of Microbiology and Immunology
Publisher
Akademiai Kiado RT
Citation
Niemz, Jana et al. “The Guanine-Nucleotide Exchange Factor CalDAG GEFI Fine-Tunes Functional Properties of Regulatory T Cells.” European Journal of Microbiology and Immunology 7, 2 (June 2017): 112–126 © 2017 The Author(s)
Version
Final published version
Abstract
Using quantitative phosphopeptide sequencing of unstimulated versus stimulated primary murine Foxp3(+) regulatory and Foxp3(-) conventional T cells (Tregs and Tconv, respectively), we detected a novel and differentially regulated tyrosine phosphorylation site within the C1 domain of the guanine-nucleotide exchange factor CalDAG GEFI. We hypothesized that the Treg-specific and activation-dependent reduced phosphorylation at Y523 allows binding of CalDAG GEFI to diacylglycerol, thereby impacting the formation of a Treg-specific immunological synapse. However, diacylglycerol binding assays of phosphomutant C1 domains of CalDAG GEFI could not confirm this hypothesis. Moreover, CalDAG GEFI(-/-) mice displayed normal Treg numbers in thymus and secondary lymphoid organs, and CalDAG GEFI(-/-) Tregs showed unaltered in vitro suppressive capacity when compared to CalDAG GEFI(+/+) Tregs. Interestingly, when tested in vivo, CalDAG GEFI(-/-) Tregs displayed a slightly reduced suppressive ability in the transfer colitis model when compared to CalDAG GEFI(+/+) Tregs. Additionally, CRISPR-Cas9-generated CalDAG GEFI(-/-) Jurkat T cell clones showed reduced adhesion to ICAM-1 and fibronectin when compared to CalDAG GEFI-competent Jurkat T cells. Therefore, we speculate that deficiency in CalDAG GEFI impairs adherence of Tregs to antigen-presenting cells, thereby impeding formation of a fully functional immunological synapse, which finally results in a reduced suppressive potential.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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DOI of Published Version
https://doi.org/10.1556/1886.2017.00007
