Refining the Characterization of DOCK11 Immune-Related Actinopathy

Lay summary of project 

Primary immunodeficiencies with early-onset autoimmunity represent a major unmet medical need, with curative options critically lacking. The dedicator-of-cytokinesis type D (DOCK D) family has emerged as a new monogenic cause of severe immune dysregulation. While actin-related defects are increasingly recognized in immune dysregulation, the specific immunological roles of DOCK D proteins remain poorly characterized. Understanding their individual and collective contributions to T cell function is critical for improving diagnosis and therapeutic strategies in this underexplored PID subgroup.

Our team established DOCK11 as the first DOCK D actinopathy and have assembled a pediatric cohort carrying mutations of DOCK11 pediatric patients — with early-onset immune dysregulation. This project will deliver the first integrative characterization of DOCK 11 deficiency through high-resolution immune phenotyping, cytokine profiling, targeted CRISPR knock-out in primary T lymphoblasts, interactome mapping, and structural modeling. By unraveling member-specific pathogenic mechanisms, we will define novel diagnostic biomarkers and rationally guide targeted therapy and hematopoietic stem-cell transplantation for these vulnerable patients.

Our objectives are to: (1) define the immune phenotype and cytokine signature of DOCK11 patients; (2) dissect the individual contributions of DOCK11 through targeted knock-out in primary T lymphoblasts; (3) identify novel diagnostic biomarkers and therapeutic targets, including potential indications for immunoglobulin therapy in DOCK11.

Brief biography

Dr Camille Lefevre is a French scientist and postdoctoral researcher in immuno-metabolism. She has an extensive expertise in lipid metabolism, immune cells, adipose tissue and stem cells, and inflammatory associated diseases. She performed her master 2 in cardiovascular, metabolism and nutrition (Université Lyon 1) in CarMeN laboratory at Lyon where she obtained a ministerial doctoral fellowship to work on the functional exploration of adipose stem cells (immunosuppression toward T cells and macrophages, and metabolism at the onset of obesity associated diseases) in the Hubert Vidal’s team in Lyon, under the supervision of Anne Mey. She highlights an immunosuppressive role of subcutaneous adipose stem cells towards T cells and that visceral ASC inhibits TNFa expression by macrophage while releasing higher level of IL6. These depot specific differences may contribute to the onset of low-grade inflammation in visceral adipose tissue prior to its onset in subcutaneous adipose tissue. She obtained her PhD in May 2020. To build her experience on adipose tissue-related diseases, inflammation and lipid metabolism, she joined in 2020, Laure Bindels’ team in MNut laboratory (UCLouvain, Belgium). Her postdoctoral works focused on the lipid reprogramming of tumor cells and their role in induction of fat depletion. In this context, she co-designed and managed the TuLip clinical study. She also pursued research on the role of microbiota in cancer cachexia and metabolism; she coauthored two reviews on this thematic. She highlights the role of tumoral acidosis in induction of fat mass depletion in cancer cachexia. She demonstrates that dampening acidosis in vivo inhibits fat depletion in murine models. She revealed a set of well-known prolipolytic and pro-inflammatory factors enhanced upon acidosis adaptation and unraveled a role of beta-glucuronidase as a promising new pro-lipolytic mediator. Her works has been awarded by the cancer cachexia society and the international society for cancer metabolism.In January 2025, she joined the Frédéric Rieux-Laucat’s lab at Institut Imagine to better characterize the DOCK D associated actinopathies with primary immune deficiency and dysregulation. A deeper understanding of these variants is crucial to improve diagnosis and may help guide treatment decisions, including the use of cell therapy or immunotherapy. Her project aims to address these challenges.