Neuro-Immunology

We are currently witnessing the emergence of a body of evidence that document novel functions of the immune system, interacting with other complex organ systems to maintain tissue homeostasis independently of pathogen challenge. Recent advances have now provided key findings that the immune system also acts as a tissue rheostat that continually senses homeostatic perturbations and contributes to organ steady state physiology.

We have recently identified a population of γδ T cells that infiltrate the lymphatics within the dura matter of the brain meninges. We demonstrated that this subset is a major source of IL-17, which promotes short-term memory by increasing neuronal synaptic plasticity in the hippocampus. On the other hand, we further reported a significant increase of meningeal IL-17 producing cells, which triggers the onset of cognitive decline in a mouse model of Alzheimer’s Disease. We thus postulate a dual role for IL-17: pro-cognitive at steady state and anti-cognitive in the context of neurodegeneration, and highlight that a tight regulation of the levels of meningeal IL-17 is critical to maintain brain integrity. These considerations led us to raise neuroscience questions under an innovative immunological angle:

• How are IL-17 levels finely tuned to guarantee optimal cognitive functions?

We are assessing the impact of environmental cues using diverse approaches such as system pharmacological manipulation, surgical ablation and specific genetic mouse models. As experimental read-out, we mostly use flow cytometry to analyze tissue immune landscape (focusing on IL-17 producers), as well as RNA sequencing to pioneer subset transcriptional profiling at single-cell resolution.

• What is the impact of IL-17 regulation on tissue pathophysiology?

We are unveiling novel neurophysiological processes under the regulation of IL-17 in the central and peripheral nervous system, namely focusing on learning and memory, anxiety, sleep and nerve regeneration. For this, we use genetic mouse models, microscopy, behavioral assays and electrophysiology.

Immuno-Oncology

In our Immuno-Oncology research line, which has been funded by the “la Caixa” Foundation, the European Molecular Biology Organization, Fundação para a Ciência e a Tecnologia and Takeda Inc, we study cellular and molecular crosstalks within the tumor microenvironment (TME), aiming to boost anti-tumor mechanisms (based on cytotoxicity and interferon-gamma secretion) over pro-tumor effects (linked to inflammation and angiogenesis). Moreover, we have translated the seminal knowledge we produced on gamma-delta (γδ) T cells to the development of a new methodology for adoptive cell therapy of cancer – Delta One T (DOT) cells – within a spin-off company, Lymphact SA, acquired in 2018 by GammaDelta Therapeutics (London, UK), and now part of Takeda Inc immunotherapy portfolio. In our team, we continue to study DOT cells, their functional regulation iwithin tumors, and their molecular mechanisms of tumor cell recognition, in collaboration with Takeda Inc.

We also conduct a more fundamental Immuno-Biology research line, which has been funded by Starting and Consolidator Grants from the European Research Council (ERC), where we focus on the thymic development and functional differentiation of gamma-delta (γδ) T cells. We aim to identify new molecular mechanisms involved in their thymic generation and in peripheral immune responses to infections (such as malaria) and cancer.

2024/2027: Novel regulators of gamma-delta T cell subset differentiation and activation in infection. Coordinator: Bruno Silva-Santos. Funding Agency: “La Caixa” Banking Foundation.

2024/2026: Dissecting the impact of the tumour microenvironment on Delta One T cells towards maximizing their therapeutic potential in colorectal cancer. Coordinator: Sofia Mensurado. Funding Agency: Liga Portuguesa Contra o Cancro.

2023/2025: Deciphering the role of IL-17 on peripheral nerve regeneration. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2023/ 2025: Optimizing Vdelta1 gamma-delta T cells for cancer immunotherapy. Coordinator: Bruno Silva-Santos. Funder: Takeda Development Center Americas, Inc.

2021/2024: Regulation of gamma-delta T cells in the tumor microenvironment. Coordinator: Bruno Silva-Santos. Funding Agency: Fundação para a Ciência e a Tecnologia.

Sumaria N, Fiala GJ, Inácio D, Curado-Avelar M, Cachucho A, Pinheiro R, Wiesheu R, Kimura S, Courtois L, Blankenhaus B, Darrigues J, Suske T, Almeida ARM, Minguet S, Asnafi V, Lhermitte L, Mullighan CG, Coffelt SB, Moriggl R, Barata JT, Pennington DJ, Silva-Santos B (2024) Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms. Nat Immunol. 25(7):1207-1217

Mensurado S, Condeço C, Sánchez-Martínez D, Shirley S, Coelho RML, Tirado N, Vinyoles M, Blanco-Domínguez R, Barros L, Galvão B, Custódio N, Gomes da Silva M, Menéndez P, Silva-Santos B (2024) CD155/PVR determines acute myeloid leukemia targeting by Delta One T cells. Blood. 143(15):1488-1495

Papotto PH, Yilmaz B, Pimenta G, Mensurado S, Cunha C, Fiala GJ, Gomes da Costa D, Gonçalves-Sousa N, Chan BHK, Blankenhaus B, Domingues RG, Carvalho T, Hepworth MR, Macpherson AJ, Allen JE, Silva-Santos B (2023) Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner. Cell Rep. 112074

Gordino G, Pereira S, Corredeira P, Borges P, Costa L, Gomes A, Silva-Santos B, Ribot JC (2022) MicroRNA-181a restricts human γδ T cell functional differentiation by targeting Map3k2 and Notch2. EMBO Rep. 23

Sánchez-Martínez D, Tirado N, Mensurado S, Martínez-Moreno A, Romecín P, Gutiérrez-Agüera F, Correia DV, Silva-Santos B*, Menéndez P* (2022) Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in acute myeloid leukemia. J Immunother Cancer. 10(9)

Brigas HC, Ribeiro MR, Coelho JR, Gomes R, Gomez V, Faivre E, Pereira S, Almeida AA, Buée L, Pousinha PA, Blum D, Silva-Santos B, Lopes LV*, Ribot JC* (2021) IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Rep. 36:109574

Wilharm A*, Brigas HC*, Sandrock I, Ribeiro M, Amado T, Reinhardt A, Demera A, Hoenicke L, Strowig T, Carvalho T, Prinz I**, Ribot JC** (2021) Microbiota-dependent expansion of testicular IL-17-producing Vγ6+ γδ T cells upon puberty promotes local tissue immune surveillance. Mucosal Immunol. 14:242–252

Lopes N*, McIntyre C*, Martin S*, Raverdeau M*, Sumaria N, Kohlgruber A, Fiala G, Dyck L, Kellis M, Brenner M, Argüello RJ, Silva-Santos B**, Pennington DJ**, Lynch L** (2020) Distinct metabolic programs established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments. Nat Immunol. 22:179–192

Ribot JC*, Lopes N*, Silva-Santos B (2020) γδ T cells in tissue physiology and surveillance. Nat Rev Immunol. 21(4):221-232

Ribeiro M*, Brigas HC*, Temido-Ferreira M, Omenetti S, Stockinger B, Waisman A, Lopes LV, Silva-Santos B, Ribot JC (2019) Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 4(40)

2022 Scientific Prize from Universidade de Lisboa, awarded to Bruno Silva-Santos.

2020 Pfizer Award in Basic Research, awarded to Julie Ribot and co-authors.

2019 Bruno Silva-Santos was elected Member of EMBO (European Molecular Biology Organization) .

2019 AstraZeneca Faz Ciência Award in Oncology (2019), awarded to Bruno Silva-Santos and Noella Lopes

2018 Prémio Janssen Inovação, awarded to Sofia Mensurado, Karine Serre and Bruno Silva-Santos.

2017 Prémio BIAL de Medicina – 2nd Prize, awarded to Bruno Silva-Santos.

2016 Scientific prize from Universidade de Lisboa, awarded to Bruno Silva-Santos.

INFARMED research award in oncoimmunology (Fundo de Investigação Saúde) awarded to Julie Ribot.

2015 Bruno Silva-Santos was nominated Honorary Member of the European Academy of Tumor Immunology.

2010 Bruno Silva-Santos was selected to the EMBO Young Investigator Programme.

2010 2nd Prize of the CESPU International Award to Julie Ribot, Ana de Barros and Bruno Silva-Santos.

2009 2nd Young Investigator Prize of the International Cytokine Society to Bruno Silva-Santos.

2009 1st Post-Doctoral Prize of the International Cytokine Society to Julie Ribot.

2009 Pfizer Award in Clinical Research to Bruno Silva-Santos.

2009 Best Paper Award (Sociedade Portuguesa de Imunologia), awarded to Julie Ribot et al.

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