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Acteria Doctoral prize in Immunology

Dr. Marta Jordāo

Marta JORDAO, DGfI, for her PhD thesis on the ontogeny, fate and function of central nervous system myeloid cells during homeostasis and neuroinflammation

Marta Jordāo, 34, received her BSc. in Genetics and Biotechnology from the University of Trás-os-Montes and Alto Douro (Portugal) and her MSc. in Cellular and Molecular Biology with specialization in Neuroscience from the University of Coimbra (Portugal). Subsequently, she obtained her PhD in Neuroimmunology in the lab of Prof. Dr. Marco Prinz at the University Medical Center of Freiburg (Germany). During her PhD, Marta Jordāo’s research focused on deciphering the origin of Central Nervous System (CNS) macrophages during health and to understand how diverse CNS myeloid cell populations acted during neuroinflammation, specifically in the context of Multiple Sclerosis (MS). Her thesis work was published in Nature Immunology and Science.

The CNS harbors different myeloid cell populations during homeostasis, mostly composed of microglia (MG) within the CNS parenchyma, as well as CNS border-associated macrophages (BAMs; comprising leptomeningeal, perivascular and choroid plexus macrophages) at the CNS interfaces. These cells are not only critical for CNS development but also for the maintenance of homeostasis and response to inflammation. Therefore, it is essential to accurately identify their cellular origins and the potential microenvironmental cues that regulate their different phenotypes. In striking contrast to what had been previously believed, Marta Jordāo and her colleagues could prove that BAMs are embryonically derived from the yolk-sac progenitors and seed the brain at early stages of embryonic development with their development and survival being independent of the transcription factor MYB. Moreover, during adulthood, they found that both perivascular and meningeal macrophages do not rely on exchange with blood monocytes to sustain their macrophage pool. Their study thus completely changed our understanding of the brain macrophage compartment and CNS immunosurveillance under healthy conditions. The recognition that there are long-lived perivascular and meningeal macrophages at the CNS barriers opened new avenues for their roles and potential manipulation in both health and disease.

While the naïve CNS is mainly populated by tissue-resident macrophages, myeloid cell complexity increases considerably during neuroinflammation. In the context of MS, the reactivation of T cells by local CNS-associated antigen-presenting cells (APCs) is crucial for disease induction. In this regard, not only BAMs but also dendritic cells (DCs) and infiltrating monocyte-derived cells (MdCs), have emerged as potential APCs in vivo. However, due to the phenotypic similarities between these myeloid populations during neuroinflammation, their discrimination was often inaccurate and did not allow a proper assessment of their functions. To unravel the extent of the myeloid contribution to the disease onset and progression, Marta Jordāo and her colleagues have analyzed each of the CNS microanatomical niches by single-cell RNA sequencing. A unique core gene signature for all BAMs was identified for the first time. Besides resident macrophages, MdCs and DCs were observed to invade the CNS compartments at very early stages of the disease. Two-photon in vivo imaging demonstrated the higher aptitude for CCR2+ cells (composed of both MdCs and DCs) to interact with T cells in comparison to resident MG and BAMs. Moreover, although CNS-resident macrophages have antigen-presenting capacity, CD11c+CCR2+ MdCs/DCs have the predominant role for T cell reactivation and consequent onset of the pathology. These data suggest that blocking specific CD11c+ cell subsets could be used for targeted therapeutic interventions. In sum, this work provided crucial new insights regarding the source of antigen presentation in the context of MS and the discrimination of different CNS myeloid subsets that can act as potential targetable cell populations in MS patients.

Dr. Marta Jordāo is currently doing her postdoc in the lab of Prof. Johanna Joyce at the University of Lausanne (Switzerland). She was awarded an EMBO long-term postdoctoral fellowship (2019-2020) and a Human Frontier Science Program postdoctoral fellowship (2020-2023) for her research work. She is currently deciphering the role of tumor-associated macrophages and CNS lymphatics in the formation and progression of glioblastoma and brain metastasis.