Biology subjects

Mertz, P.

Publications and source records attributed to Mertz, P..

3 recordsLinked to original sources

bioRxiv2024

Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice

STING gain-of-function (GOF) mutations are associated with the severe autoinflammatory disease designated STING Associated Vasculopathy with onset in Infancy (SAVI). Mice with the STING GOF V154M mutation develop profound T cell lymphopenia, partly due to a blockage of T cell development in the thymus. To better characterize the mechanisms of peripheral T cell dysfunctions, we conducted a transcriptomic and phenotypic analysis on sorted splenic CD4+ and CD8+ mature T cells from STING GOF V154M mice. We identify a T cell exhaustion phenotype that manifests at a terminal stage, acquired early in life but only after reaching the peripheral environment. This phenotype is independent of type I interferons and does not rely on intrinsic STING activation in either T cells or stromal cells. Mechanistically, the limited number of mature T cells that reach the periphery appear to be quickly impacted by the lymphopenic environment, experiencing heightened stimulation of the IL-7 receptor and TCR pathways, including the NFAT pathway, a key factor in T cell exhaustion. By performing transplantation experiments with STING GOF long term-hematopoietic stem cells (LT-HSCs) along with supportive wild-type bone marrow (BM) cells, we were able to prevent the T cell exhaustion of STING GOF T cells in the resulting non-lymphopenic context, demonstrating that lymphopenia is a major driver of T cell exhaustion in STING GOF mice. T cell exhaustion, although less severe, was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results, which highlight T cell exhaustion induced by lymphopenia, could have important implications for the management of patients with severe immune deficiencies. HighlightsO_LIWe describe a phenotype of T cell exhaustion in STING GOF V154M mice, which is acquired early in life and in the periphery. C_LIO_LISTING GOF-associated T cell exhaustion is independent of type I IFNs, and STING GOF/activation in T cells or in stromal cells is not sufficient for T cell exhaustion. C_LIO_LILymphopenia is a major driver of T cell exhaustion in STING GOF mice, and increased antigenic/IL-7 stimulation of T cells in the lymphopenic context of STING GOF mice could be implicated in the induction of T cell exhaustion. C_LI

immunology↗

bioRxiv2024

C-terminal CDC42 variants in autoinflammatory patients specifically trigger actin defects and NF-kB hyperactivation

BackgroundCDC42 belongs to the RHO GTPases family. Recently, four variants were identified in autoinflammatory patients. One variant affects the N-terminal part of the protein while the three others are located in the C-terminal region. To date, most of the functional defects were only reported for the C-terminal R186C variant. The other three variants are far less characterized at the functional level. ObjectivesWe aimed to investigate whether all four CDC42 variants share common signaling alterations. MethodsWe performed in depth imaging analysis of actin cytoskeleton and NF-{kappa}B nuclear translocation, coupled to flow cytometry in cells from patients or in the monocytic THP-1 cell line. ResultsWe show that the N-terminal Y64C CDC42 variant localizes normally in cells and does not exhibit any defect in actin filaments formation or NF-{kappa}B activation. By contrast, all three C-terminal CDC42 variants have aberrant subcellular localizations and share common functional alterations. They exhibit a strong reduction or complete block in their abilities to polymerize actin filaments. They also show more NF-{kappa}B nuclear translocation and phosphorylation. However, we suggest that there is no causal relationship between these two events. Artificial reduction in cellular actin content using specific pharmacologic drugs is indeed not sufficient to hyperactivate NF-{kappa}B. ConclusionsThis study further extends the spectrum of defects observed in autoinflammatory CDC42 patients, and pinpoints a functional heterogeneity between N- and C-terminal CDC42 variants. We also show that CDC42 patients should not be necessarily classified among actinopathies. Altogether, the functional defects we report here can lead the way towards more personalized therapeutic interventions.

immunology↗

bioRxiv2024

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called "noncanonical" autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly in ATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment. Key messagesO_LIPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE C_LIO_LIWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc C_LIO_LIWe show here that autophagy is comparable between PBMCs from patients and matched controls C_LIO_LIWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients C_LIO_LIAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation C_LI

immunology↗