Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

Cornelia Scharler, Rodolphe Poupardin, Patricia Ebner-Peking, Martin Wolf, Christina Schreck, Gabriele Brachtl, Andre Cronemberger Andrade, Linda Krisch, Laurence Daheron, Katharina Schallmoser, Karsten Jürchott, Judit Küchler, Harald Stachelscheid, Hans Dieter Volk, Robert A.J. Oostendorp, Dirk Strunk

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Stromal cells interact with immune cells during initiation and resolution of immune responses, though the precise underlying mechanisms remain to be resolved. Lessons learned from stromal cell-based therapies indicate that environmental signals instruct their immunomodulatory action contributing to immune response control. Here, to the best of our knowledge, we show a novel function for the guanine-exchange factor DOCK2 in regulating immunosuppressive function in three human stromal cell models and by siRNA-mediated DOCK2 knockdown. To identify immune function-related stromal cell molecular signatures, we first reprogrammed mesenchymal stem/progenitor cells (MSPCs) into induced pluripotent stem cells (iPSCs) before differentiating these iPSCs in a back-loop into MSPCs. The iPSCs and immature iPS-MSPCs lacked immunosuppressive potential. Successive maturation facilitated immunomodulation, while maintaining clonogenicity, comparable to their parental MSPCs. Sequential transcriptomics and methylomics displayed time-dependent immune-related gene expression trajectories, including DOCK2, eventually resembling parental MSPCs. Severe combined immunodeficiency (SCID) patient-derived fibroblasts harboring bi-allelic DOCK2 mutations showed significantly reduced immunomodulatory capacity compared to non-mutated fibroblasts. Conditional DOCK2 siRNA knockdown in iPS-MSPCs and fibroblasts also immediately reduced immunomodulatory capacity. Conclusively, CRISPR/Cas9-mediated DOCK2 knockout in iPS-MSPCs also resulted in significantly reduced immunomodulation, reduced CDC42 Rho family GTPase activation and blunted filopodia formation. These data identify G protein signaling as key element devising stromal cell immunomodulation.

Original languageEnglish
Article number1246
JournalCommunications Biology
Issue number1
StatePublished - Dec 2022
Externally publishedYes


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