T cells play crucial roles in immune response against pathogens and tumors. However, T cells are also a major cause of chronic inflammation driving autoimmunity and HIV-1 infection. Our lab aims to illuminate the role of (mis)communication between T cells and the tissue microenvironments in the development of human chronic inflammatory diseases. The best way to provide insights to human disease that can be readily translatable into revolutionary new therapies is to study directly the pathological processes in patients. Using tissue samples from patients we are pursuing how biological variables such as gender/sex, infectious agents, autoimmune diseases, and tissue microenvironment impinge on the signaling and metabolic circuitry of T cells driving the chronic inflammation and pathology.
To cover the multiple facets of human disease we have established an interdisciplinary approach combining: clinical, bioinformatics, cellular and molecular immunology and cutting-edge microscopy. A better knowledge of the complex interactions between genetic, immunological and environmental factors will lead to the ultimate goal: to develop new approaches that will allow for patient stratification and to identify novel therapeutic targets that will enable the development of precision therapies.
1-Elucidate the tissue specific mechanisms that convey and/or counter-regulate chronic inflammation
Plasticity endows T cells to be influenced by their microenvironment and respond to it accordingly. A specific microenvironment is defined by a variety of factors, including biological and chemical composition, cell-cell interactions, but also metabolic and mechanical cues. Tissue injury as well as inflammatory tissue alterations lead to changes in the niche influencing the plasticity and biology of residing/incoming T cells.
1A- Reprogramming inflammatory T cells to treat autoimmune diseases
CD4 T cells are key drivers of rheumatoid arthritis (RA), the most common inflammatory rheumatic disease. Current biological treatments, including inhibition of T cell co-stimulation, are successful at managing RA in a subset of patients, but 40 % of patients do not respond to therapy. There is an unmet need for therapies that precisely target the mechanisms underpinning CD4 T cell dysregulation rather than overall T cell activation or the end products, inflammatory cytokines. In rheumatoid arthritis, elucidating how the joint microenvironment imprints dysregulated T cell inflammation, drives and possibly diversifies their pathological functions could broaden the potential therapeutic targets, extending beyond the successful blockade of end-stage inflammatory mediators.
Our research breaches immunology and clinical studies. We start with clinical data and tissue samples from patients and probe for the cellular and molecular mechanisms involved. This research line focuses on defining the basis and consequences of pathogenic T cell populations in the development of Rheumatoid Arthritis. It combines high-throughput studies to identify genes/drug targets with molecular and cellular characterization of pathogenic T cell populations through multiparameter flow cytometry and advanced microscopy. Additionally, tissue explants will be used to elucidate the role of tissue microenvironment in driving joint chronic inflammation.
1B- Homeostatic regulation of T cell plasticity by the tissue microenvironment
Using blood T cells from healthy donors and exposing them to particular tissue microenvironment conditioning, we are unveiling the cellular and molecular mechanisms by which tissue microenvironment counter-regulates T cell inflammatory profile conducive to tissue homeostasis/repair.
2- Tackling HIV-1 follicular reservoirs: from HIV-1 genetic diversity to sex-biased immune responses
The compounded contribution of host intrinsic factors, immunological niches and viral genetic diversity to HIV-1 pathogenesis remain largely unknown. First, sex has been a neglected host intrinsic variable, yet women display faster HIV disease progression. Second, the immunological niche offered by follicular T (Tfh) cells allows for HIV-1 ongoing replication even in successfully treated patients. Finally, most of current knowledge on HIV-1 pathogenicity is based on the study of the fairly infrequent subtype B. The mechanisms underlying HIV-female bias, the establishment of Tfh replicating reservoirs and how HIV-genetic diversity impinge on pathogenicity remain largely undefined. We are addressing HIV-1 infection as a continuum of host intrinsic biological factors, immunological niches and HIV-1 genetic diversity.
2A- Eradicating HIV-1 follicular sanctuaries through immunotherapy
HIV-1 is primarily an infection of lymphoid tissues. Anti-retroviral therapy (ART) has rendered HIV-1 infection a manageable illness for those with access to treatment, still it does not clear reservoirs where the virus persists. Follicular helper T (Tfh) cells were recently identified as the major source of ongoing HIV-1 replication even in ART-treated patients. To dissect cellular and molecular characteristics of the follicular reservoir we are using human follicular T cells isolated from human tonsils through fluorescence-activated cell sorting (FACS) and infect them ex vivo with HIV-1. We are pursuing the identification, at the molecular level, the activation and metabolic pathways hijacked by HIV-1 through a combination of flow cytometry, metabolic assays and confocal analysis.
2B- Sex-biased T cell immunity and HIV-1 pathogenicity
Women mount stronger immune responses and experience more severe HIV-1 pathogenesis. The precise mechanism mediating the sexual dimorphism in HIV-1 pathogenesis is not known, partly because sex has not been considered a biological variable. Using human blood and tonsillar samples, we aim at identifying the molecular determinants underpinning the interplay between sex hormones and HIV-1 infection in order to identify potential pathways for intervention, and to rationally control for biological differences relevant to therapeutic efficacy outcomes.
2C- Impact of HIV-1 genetic diversity in immunodeficiency
HIV-1 genetic diversity explains 29% of the variation in disease severity, while host factors explain 8.4% (9). Even though it only accounts for ~10% of worldwide HIV-1 infections, the subtype B constitutes the almost exclusive source of HIV-1 laboratory studies. However, distinct HIV-1 subtypes have different biological properties including disease progression rates and cellular tropism. The impact of HIV genetic diversity can only be optimally undertaken in countries with high HIV genetic diversity through first-rate clinical registry.
In Angola, we are sequencing HIV-1 mutations found in newborn and mother samples and associating them to drug resistance. This study goal is to be able to adjust the ART regimen of these newborns and their mothers to their HIV-1 sequences and will improve the quality of life of Angolan children.
In our Portuguese cohort (in collaboration with Nuno Osório at Universidade do Minho), we are incorporating HIV phylogenetic and computational prediction of molecular evolution and immunogenicity analysis with immunovirological approaches to dissect the impact of HIV-genetic variability on HIV-pathogenesis and tropism for Tfh reservoirs.
-Project from European Society for Clinical Microbiology and Infectious Diseases (ESCMID)- 2019
"Decoding immunometabolism to thwart HIV-1 follicular reservoir"
PI: Sofia A. Cerqueira
Supervisor: Helena Soares
“Reprogramming inflammatory-follicular T cells (Tfhi): from the clinic to precision immunotherapies”
PI: Helena Soares
Co-PI: Jaime C. Branco
-Gilead Génese de 2018
PI: Nuno Osório, ICVS, Universidade do Minho
Co-PI: Helena Soares, CEDOC
- NOVA Saúde Grant
PI: Ana Petronilho, ITQB, Universidade NOVA de Lisboa
Co-PI: Helena Soares, CEDOC
PI: Fernando Pimentel-Santos, Hospital Egas Moniz and CEDOC
Co-PI: Helena Soares, CEDOC
- Gilead Génese: April 2017-March 2019
“HIV-1 Replication in Follicular Sanctuaries”.
- Investigador FCT 2014-2019
- ANRS (French AIDS Research Foundation) Grant: 2013-2015
- Silva JG, Martins NP, Henriques R, Soares H. (2016) HIV-1 Nef Impairs the Formation of Calcium Membrane Territories Controlling the Signaling Nanoarchitecture at the Immunological Synapse.. Journal of Immunology. 2016. 197 (10): 4042-4052; selected to be highlighted “In this Issue” of The Journal of Immunology
- Soares H*. HIV-1 intersection with CD4 T cell vesicle exocytosis: intercellular communication goes viral. Frontiers in Immunology. 2014. 5:454 doi: 10.3389/fimmu. (*Corresponding author)
- Soares H, Lasserre R, Alcover A. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses. Immunological Reviews. 2013. 256(1): 118-13
- Soares H*, Henriques R, Ventimiglia L, Alonso MA, Zimmer C, Thoulouze MI, Alcover A*. A regulated vesicle fusion cascade generates signaling nanoterritories that control T-cell activation at the immunological synapse. Journal of Experimental Medicine. 2013. 210(11): 2415-33. Selected for 1000Prime as being of special significance in its field; highlighted on Journal of Cell Biology and on Journal of General Physiology (*Corresponding authors)
- Herbert S, Soares H, Zimmer C, Henriques R. Single-molecule super-resolution microscopy: deeper and faster. Microscopy and Microanalysis. 2012. 18(6): 1419-29
- Soares H, Waechter H, Glaichenhaus N, Mougneau E, Yagita H, Mizenina O, Dudziak D, Nussenzweig MC, Steinman RM. A subset of Dendritic cells induces CD4+ T cells to produce IFN- by an IL-12-independent but CD70-dependent mechanism in vivo. J. Exp. Med. 2007. 204 (5): 1095-1106
- Trumpfheller C, Finke JS, Lopez CB, Moran TM, Moltedo B, Soares H, Huang Y, Schlesinger SJ, Park CG, Nussenzweig MC, Granelli-Piperno A, Steinman RM. Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. J. Exp. Med. 2006. 203 (3): 607-617
- Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H, Brimmes MK, Moltedo B, Moran TM, Steinman RM. In vivo targeting of antigens to maturing dendritic cells via DEC-205 receptor improves T cell vaccination. J. Exp. Med. 2004. 199(6): 815-824
- Andrade LCR, Paixão JA, de Almeida MJM, Martins RML, Soares HIM, Moreno MJSM, Sá e Melo ML, Campos Neves AS. 16, 17-Epoxy-20-oxopregn-5-ene-3b, 21-diyl diacetate. 2003. Acta Crystallogr. (E) E59: 299-301.
- Andrade LCR, Paixão JA, de Almeida MJM, Martins RML, Soares HIM, Moreno MJSM, Sá e Melo ML, Campos Neves AS. 16-Hydroxi-20-oxopregn-5-en-3-yl acetate. 2001. Acta Crystallogr. (E) E57: 571-57
- Andrade LCR, Paixão JA, de Almeida MJM, Martins RML, Soares HIM, Morais GJR, Moreno MJSM, Sá e Melo ML, Campos Neves AS. 1617-Epoxi-20-oxopregn-5-en-3-yl acetate. 2001. Acta Crystallogr. (C1) C57: 587-589
- Jaime Branco - Rheumatological Diseases Unit CEDOC|FCM, Lisbon, Portugal
- Fernando Pimentel-Santos - Rheumatological Diseases Unit CEDOC|FCM, Lisbon, Portugal
- Ana Filipa Mourão - Hospital Egas Moniz, CHLO, Lisbon, Portugal
- Cristina Caroça - CUF, Lisbon, Portugal
- Ricardo Henriques - Quantitative Imaging and NanoBioPhysics Group, UCL, London, UK
- Paula Videira - Laboratory of Glycoimmunology, Faculdade de Ciências e Tecnologia, Caparica, Portugal
- Robert Weil - Laboratory of Signalling and Pathogenesis, Institut Pasteur, Paris, France
- Nuno Osório, Instituto de Investigação em Ciências da Vida e da Saúde (ICVS), Universidade do Minho, Braga, Portugal
- Ricardo Silvestre, Instituto de Investigação em Ciências da Vida e da Saúde (ICVS), Universidade do Minho, Braga, Portugal
- Herédio de Sousa, Hospital Dona Estefânia, Lisboa, Portugal
- Ana Petronilho, Instituto de Tecnologia e Química Biológica (ITQB), Universidade NOVA de Lisboa, Lisboa, Portugal
We welcome motivated technicians, students (undergraduates, master and PhD) and post-docs to join our lab. For enquiries on available positions contact Helena Soares (helena.soares(at)nms.unl.pt). Please add a letter detailing the reasons you are applying, your CV, and contact information of 3 references.