The impact of dynamic interactions between meningeal immune cells on neurodevelopment
The meninges represent neurotrophic and immunologically active membranes between the surface of the brain and the skull. Recent data show that during neurodevelopment, T cells and macrophages progressively populate the meninges, interact, and are likely to promote brain growth by providing neurotrophic factors. This occurs in parallel to a developmental increase of the intracranial pressure and an increase in extracellular matrix stifness that could promote those neurotrophic interactions. The objective of this project is to understand if the mecanical context of neurodevelopment favors meningeal macrophages (MM) interaction with T cells. To this end, we will combine physical and biological strategies to visualize, manipulate and characterize the interactions between MM and T cells in vitro, under different conditions of pressure and at different developmental times. We will extend our results in vivo in mice models. This pioneering work will help to understand how physical cues guide interactions between neuroimmune cells.
Neurodevelopment, T cells, meningeal macrophages, mechanotransduction, pressure, chemoattraction.
1. Define the dynamics of MM and T cells interactions in different pressure and matrix stiffness contexts
2. Define the consequences of macrophages and T cells contact in terms of activation (calcium induced-production of neurotrophic factors, chemokines, cytokines, vasoactive peptides, ...)
3. Understand the molecular mechanisms allowing MM-T cell contact and signal transduction
4. Evaluate the in vivo relevance of our findings in neurodevelopment
Proposed approach (experimental / theoretical / computational)
Preliminary data indicate that MM express integrins and chemoattractants even in the steady state. They are also equipped with mechanoreceptors that are activated by an increase in hydrostatic pressure.
1/ We will analyse MM and T cell populations ex vivo under neonatal (1mmHg) and adult (5mmHg) pressure conditions, and on neonatal and adult meningeal matrix.
2/ We will develop algorithms to quantify their physical interactions (contact time, trajectory, chemoattraction) and to correlate cell-cell interactions and its consequences (calcium, ...)
3/ We will perform single-cell RNA sequencing of MM and T cells in different conditions pressure/stiffness. Neurotrophic outputs will be analysed in silico and validated in vitro.
4/ We will use knock-out mice and transcranial inhibition of receptors during neurodevelopment to block these physical interactions, and measure its impact on brain development.
This project is interdisciplinary as it requires:
1- The expertise of Dr. Valignat in the LAI lab. She optimized the tracking of T cell migration and set up chemokine and pressure-controlled assays that will be important to understand MM-T cells interactions.
2- The neurology and immunopathology expertise of Dr. Rua. She has already described the key virological and immunological parameters involved in the control of neuroinflammation, and we will be able to follow those parameters upon MM manipulation (inhibition of mechanosignal transduction).
3- The bioinformatics expertise of the CIML genomic facility (Dr. Rua’s Institute). In silico analysis of the upstream transcriptomic regulators of MM and T cells will be needed to infer the activation state and transduction signaling pathways involved in brain development and brain defense.
We are looking for a candidate with either a neuroscience background, or with a biophysics background. The PhD candidate should be able to learn fast and adapt to different environments. He/She should be fluent in English or/and French.
Is this project the continuation of an existing project or an entirely new one? In the case of an existing project, please explain the links between the two projects
This is a new project.
2 to 5 references related to the project
- Multifaceted interactions between adaptive immunity and the central nervous system.
Science. 2016 Aug 19;353(6301):766-71. doi: 10.1126/science.aag2638.
- Unraveling the mechanobiology of immune cells.
Zhang X, Kim TH, Thauland TJ, Li H, Majedi FS, Ly C, Gu Z, Butte MJ, Rowat AC, Li S.
Curr Opin Biotechnol. 2020 Dec;66:236-245. doi: 10.1016/j.copbio.2020.09.004. Epub 2020 Sep 30.
- Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid.
Schläger C, Körner H, Krueger M, Vidoli S, Haberl M, Mielke D, Brylla E, Issekutz T, Cabañas C, Nelson PJ, Ziemssen T, Rohde V, Bechmann I, Lodygin D, Odoardi F, Flügel A.
Nature. 2016 Feb 18;530(7590):349-53. doi: 10.1038/nature16939. Epub 2016 Feb 10.
3 main publications from each PI over the last 5 years
- Marie-Pierre Valignat
Amoeboid Swimming Is Propelled by Molecular Paddling in Lymphocytes.
Aoun L, Farutin A, Garcia-Seyda N, Nègre P, Rizvi MS, Tlili S, Song S, Luo X, Biarnes-Pelicot M, Galland R, Sibarita JB, Michelot A, Hivroz C, Rafai S, Valignat MP, Misbah C, Theodoly O.
Biophys J. 2020 Sep 15;119(6):1157-1177. doi: 10.1016/j.bpj.2020.07.033. Epub 2020 Aug 12.
- Lymphocytes perform reverse adhesive haptotaxis mediated by LFA-1 integrins.
Luo X, Seveau de Noray V, Aoun L, Biarnes-Pelicot M, Strale PO, Studer V, Valignat MP, Theodoly O.
J Cell Sci. 2020 Aug 25;133(16):jcs242883. doi: 10.1242/jcs.242883.
- A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes.
Hornung A, Sbarrato T, Garcia-Seyda N, Aoun L, Luo X, Biarnes-Pelicot M, Theodoly O, Valignat MP.
Biophys J. 2020 Feb 4;118(3):565-577. doi: 10.1016/j.bpj.2019.12.013. Epub 2019 Dec 18.
- Meningeal macrophages protect against viral neuroinfection.
Rebejac J, Eme-Scolan E, Arnaud Paroutaud L, Kharbouche S, Teleman M, Spinelli L, Gallo E, Roussel-Queval A, Zarubica A, Sansoni A, Bardin Q, Hoest P, Michallet MC, Brousse C, Crozat K, Manglani M, Liu Z, Ginhoux F, McGavern DB, Dalod M, Malissen B, Lawrence T, Rua R.
Immunity. 2022 Nov 8;55(11):2103-2117.e10. doi: 10.1016/j.immuni.2022.10.005. Epub 2022 Nov 1.
- Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity.
Rua R, Lee JY, Silva AB, Swafford IS, Maric D, Johnson KR, McGavern DB.
Nat Immunol. 2019 Apr;20(4):407-419. doi: 10.1038/s41590-019-0344-y. Epub 2019 Mar 18.
- T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation.
Kwong B*, Rua R*, Gao Y, Flickinger J Jr, Wang Y, Kruhlak MJ, Zhu J, Vivier E, McGavern DB, Lazarevic V.
Nat Immunol. 2017 Oct;18(10):1117-1127. doi: 10.1038/ni.3816. Epub 2017 Aug 14.