Bruno Silva-Santos Lab
T lymphocytes play crucial roles in cellular immunity against pathogens and tumors. However, T lymphocytes can also be a major cause of autoimmunity and allergy. These (patho)physiological roles of T lymphocytes depend on their cellular and molecular activities, namely the production of cytotoxic molecules and pro- versus anti-inflammatory cytokines. In our Lab we employ in vitro and in vivo models to study the differentiation, activation and expansion (in response to infections or tumors) of murine and human T lymphocytes.
We have previously demonstrated that the development of important T lymphocyte subsets, namely gamma-delta (γδ) T cells and regulatory T cells, is orchestrated by molecular events taking place in the thymus that are highly dependent on interactions between the receptor CD27 (expressed on T cell progenitors) and its ligand CD70 (mostly present on thymic epithelial cells). Moreover, the CD27/CD70 signaling pathway is also critical for the expansion of γδ T cells in the periphery, which may be exploited in future cancer immunotherapy protocols. In this context, we have also identified novel molecular determinants of tumor cell recognition by human gamma-delta T cells, which unexpectedly are based on natural killer (NK) receptors such as NKG2D or NKp30. In the future we plan to further dissect the molecular pathways that control γδ T cell activation and tumor cell recognition. Most importantly, we aim to apply our knowledge on γδ T cells to the pre-clinical and clinical targeting of acute and chronic leukemias. Given that the major therapeutic hurdle following conventional chemotherapy consists of leukemia relapse, we will explore the possibility of using immune intervention (based on γδ T cells) to target escape variants and thus prevent cancer relapse.
» Research Areas
» Group Leader
1. T cell differentiation and activation
1.1. Role of costimulatory receptors and cytokines
1.2. Epigenetic and transcriptional regulation
1.3. MicroRNA-mediated regulation
2. Tumor immunology
2.1. Tumor cell dynamics and clonal evolution: impact on immune evasion
2.2. Tumor cell recognition via NK receptors
2.3. Tumor-promoting leukocyte subsets
» Research Team
Bruno Silva-Santos, PhD, Associate Professor (CV)
» Ongoing Research Projects
2010-2015 European Research Council, Starting Grant, Project 260352: Differentiation of pro-inflammatory T cell subsets in vivo
2014-2015 Fundação para a Ciência e Tecnologia, EXPL/IMI-IMU/0170/2013: Characterization of the molecular mechanisms of differentiation of the human γδ T cell lymphocytes
2014-2015 Fundação para a Ciência e Tecnologia, EXPL/BIM-ONC/1656/2013: Quantitative analysis of clonal evolution and characterization of the escape variants on Acute Myeloyd Leukemia relapse
2014/2016 Associação Portuguesa Conta a Leucemia, “Preprogrammed versus stochastic clonal evolution of relapsing Acute Myeloid Leukemia: Impact on disease
development and therapeutic responses”.
» Science and Society Activities
• Prof. Adrian Hayday, Cancer Research UK and King’s College London, UK
• Prof. Daniel Pennington, Blizard Institute, Queen Mary College, London, UK
• Prof. Ton Schumacher, The Netherlands Cancer Institute, Amsterdam, NL
• Prof. Jannie Borst, The Netherlands Cancer Institute, Amsterdam, NL
• Dr. Domenico Mavilio, Instituto Humanitas, Milan, Italy
• Dr. Antonella Viola, Instituto Humanitas, Milan, Italy
Receive school visits in the lab to promote science divulgation, namely to students of the second grade.
Science communications to the media (press, radio and television).
» Selected Publications
Our team has been distinguished with:
- Pfizer Award in Clinical Research (2009) to B. Silva-Santos;
- Best Paper Award from the Portuguese Society of Immunology (2009) to J. Ribot, A. deBarros, B. Silva-Santos et al.;
- 1st Post-doctoral Prize of the International Cytokine Society (2009) to J. Ribot;
- 2nd Young Investigator Award Prize of the International Cytokine Society (2009) to B. Silva-Santos;
- 2nd Prize of the CESPU International Award (2010) to J. Ribot, A. deBarros and B. Silva-Santos.
B. Silva-Santos was also selected to the Young Investigator Programme of the European Molecular Biology Organization (2010); and nominated to the Editorial Boards of OncoImmunology (2011), European Journal of Immunology (2012) and Immunity, Infection and Disease (2013).
» Useful Links
● Coquet J*, Ribot JC*, Babala N, Middendorp S, Xiao Y, Neves JF, Fonseca-Pereira D, Jacobs H, Pennington DJ, Silva-Santos B** and Borst J** (2013). Epithelial and dendritic cells in the thymic medulla promote CD4+ Foxp3+ regulatory T cell development via the CD27-CD70 pathway. Journal of Experimental Medicine 210(4):715-28 (*,**Equal contributions)
● Lança T, Souza MF, Gonçalves-Sousa N, Rei M, Grosso AR, Penido C and Silva-Santos B (2013). Protective role of the inflammatory CCR2/ CCL2 chemokine pathway through recruitment of type 1 cytotoxic γδ T lymphocytes to tumor beds. J Immunol 190(12): 6673-80.
● Hudspeth K, Fogli M, Correia D, Mikulak J, Roberto A, Della Bella S, Silva-Santos B* and Mavilio D* (2012). Engagement of NKp30 on Vδ1+ T-cells induces the production of CCL3, CCL4 and CCL5 and suppresses HIV-1 replication. Blood 119(17): 4013-6. (*Equal contributions)
● Ribot JC, deBarros A, Mâncio-Silva L, Pamplona A and Silva-Santos B (2012). B7-CD28 costimulatory signals control the survival and proliferation of murine and human γδ T cells via interleukin-2 production. J Immunol 189(3): 1202-8.
● Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D* and Silva-Santos B* (2011). Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118: 992-1001
● Mahtani-Patching J, Neves JF, Pang DJ, Stoenchev KV, Aguirre-Blanco AM, Silva-Santos B and Pennington DJ (2011). PreTCR and TCRγδ signal initiation in thymocyte progenitors does not require domains implicated in receptor oligomerization. Science Signal 4: ra47.
● Lança T., Correia D. V., Moita C. F., Raquel H., Ferreira C., Ramalho J. S., Barata J. T., Moita L. F., Gomes A. Q. and Silva-Santos B. (2010). The MHC class Ib protein ULBP1 is a non-redundant determinant of leukemia/ lymphoma susceptibility to γδ T-cell cytotoxicity. Blood: 115(12): 2407-11.
● Ribot J. C., Chaves-Ferreira M., d’Orey F., Wencker M., Gonçalves-Sousa N., Decalf J., Simas J. P., Hayday A. C. and Silva-Santos B. (2010). Cutting Edge: Adaptive versus innate signals selectively control the pool sizes of IFN-γ- or IL-17-producing γδ T cells upon infection. J Immunol: 185(11):6421-5.
● Gomes A. Q.*, Correia D. V.*, Grosso A. R., Lança T., Ferreira C., Lacerda J. F., Barata J. T., Gomes da Silva M. and Silva-Santos B. (2010). Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood γδ T cells. Haematologica: 95(8):1397-404. (*Equal contributions)
● Gonçalves-Sousa N, Ribot JC, deBarros A, Correia DV, Caramalho I and Silva-Santos B (2010). Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T-cells is cell-contact dependent and sensitive to GITR modulation. Eur J Immunol 40(1): 61-70.
● Ribot J. C., deBarros A., Pang D. J., Neves J. F., Peperzak V., Girardi M., Borst J., Hayday A. C., Pennington D. J. and Silva-Santos B. (2009) CD27 is a thymic determinant of the balance between IFN-γ- and IL-17-producing γδ T cell subsets. Nature Immunol 10: 427-436.