Workshop 2024

13:00  Badge pick up

13:15  Welcoming words

13:30  Neurodevelopment

Keynote speaker: Aleksandra Deczkowska

3 Selected Oral presentations

14:45  Neuroimmunological aspects of Multiple Sclerosis

Keynote speaker: Robin Franklin

3 Selected Oral presentations

16:00  POSTER SESSION/ Coffee Break

17:15   Nervous system Infections

Keynote speaker: Jasmine Herz

3 Selected Oral presentations

18:00 COCKTAIL/DINER

9:00  Peripheral/ Neuro-Immune Cross talk

Keynote speaker: Nicolas Gaudenzio

3 Selected Oral presentations

10:15  Neuro-immune interactions in Brain Tumors

Keynote speaker: Maria Castro

3 Selected Oral presentations

11:30  Neuroimmunological aspects of Neurodegenerative Diseases

Keynote speaker: Michael Heneka

3 Selected Oral presentations

12:45: PRIZES/ Closing words

13:00: LUNCH

Student

Free

Post-Doc

Free

PI

100€

Lennart Mars

Pasteur Lille

Nicolas Blanchard

(Infinity, Toulouse, FR)

Guillaume Dorothée

(Centre de Recherche Saint Antoine, Paris)

Violetta Zujovic

(Paris Brain Institute, ICM, Paris)

While the interaction of the adaptive and innate immune systems in the pathogenesis of autoimmune disorders of the central nervous system is well defined, the mechanisms by which microglia trigger a T cell response remain unclear. We and others reported the surprising finding that microglia in Multiple Sclerosis (MS) lesions contained intact mRNAs for myelin proteins. In this talk I will describe how, in the context of myelin debris in animal models of experimental demyelination, microglia phagocytose and process intact oligodendrocyte-encoded and exogenous mRNA transcripts in a CD36 dependent manner. We used orthologous and tagged mRNAs within myelin debris to demonstrate this combination uniquely promotes efficient uptake of mRNA, translation and presentation of proteins that leads to antigen-specific activation of adaptive CD4 and CD8 immune cells. These new data indicate that microglia phagocytose and translate mRNAs when presented with myelin debris leading to T cell activation, a novel mechanism potentially explaining propagation and even initiation of MS.

Jasmine Herz, Washington university (US)

The adaptive immune system relies on formation of the memory of past microbial challenges to accelerate protective immune responses in the event of reinfection. This memory is accomplished in part by the retention of antigen-specific B and T cells within barrier tissues. We conducted an extensive molecular and functional analysis of meningeal T cells to test the hypothesis that the meninges in the brain sense and respond to internal and external cues throughout life, and that alterations in the meningeal T cell repertoire alter brain function. Using models of pathogen exposure, we describe a neuroimmune axis in which antigen experienced resident T cell subsets dynamically record immune perturbations, which resulted in behavioral abnormalities that were exacerbated with aging. Our findings elucidate molecular properties of T cells that survey the brain borders under both homeostatic and pathological conditions and provide insights linking CNS immune surveillance with memory.

Nicolas Gaudenzio, Infinity (FR)

Maria Castro, University of Michigan Medical School (US)

Mutation in isocitrate dehydrogenase (mIDH) is a common genetic lesion encountered in glioma patients. Approximately 90% of IDH1 mutations occur in exon 4 at codon 132, resulting in a single amino acid from arginine to histidine (R132H). Less common IDH2 mutations occur in an analogous codon at position R172. IDH1/2 mutations are always heterozygous, exerting a dominant gain of function enzymatic activity which leads to the production of 2-hydroxyglutarate (2HG). Excessive 2HG production causes DNA hypermethylation via inhibition of methylcytosine dioxygenase TET2, and also promotes histone hypermethylation through competitive inhibition of α-ketoglutarate (αKG)-dependent Jumonji-C histone demethylases. This leads to epigenetic reprogramming the transcriptome within the mIDH1 glioma cells. Several studies suggested that mIDH1 may play a critical role in shaping the immunological landscape of the tumor immune microenvironment (TME). We demonstrate that mutant isocitrate-dehydrogenase 1 (mIDH1) synthetizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ immune transcriptome leading to the reversion of the glioma immunosuppressive microenvironment.

We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells compartment infiltrating the TME. We uncovered that the immature myeloid cells-infiltrating the mIIDH1 TME are mainly non-suppressive neutrophils and pre-neutrophils. Myeloid cells’ reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem-like cells. Blocking G-CSF in mIDH1 glioma-bearing mice restores the inhibitory potential of myeloid cells, accelerating tumor progression. Also, we demonstrate that G-CSF reprograms bone-marrow granulopoiesis resulting in non-inhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy. In conclusion, out results uncover an important role of mIDH1 on reprogramming the phenotypic and functional diversity of myeloid cells in glioma TME, a feature that can be harnessed to enhance the efficacy of immunotherapies in glioma patients.

Michael Heneka, Luxembourg Centre for Systems Biomedicine (LUX)

While the brain has been considered an immune-privileged organ, increasing evidence suggests that innate immune cells are intimately involved in neurodegenerative disease evolution and progression. Microglia play a pivotal role for this cerebral innate immune response and are activated by binding of protein aggregates to pattern recognition receptors. This binding may activate pathways that are involved in phagocytosis and degradation in order to protect neurons from damage. On the other hand, immune activation of microglia may lead to the release of inflammatory mediators and distracts microglia from their physiological functions and tasks. Microglial distribution of neurotoxic beta-sheet structured cargo may help stressed cells to cope with the inflammatory activation and contribute to the overall successful clearance. Importantly, disease causing mutations and risk polymorphisms for neurodegenerative disease such as Parkinson’s disease and Alzheimer’s disease are being tested for the potential to influence cargo distribution through tunneling nanotubes. Likewise, immune cells help each other by sharing intact mitochondria in order to cover the increased energy demand during an inflammatory challenge. Similar mechanisms may be in place between microglia and further brain cells including astrocytes and neurons. The capability of microglia providing such help to neighboring cells may be key to prevent neurodegeneration and represent a new therapeutic target.