Luís Graça

University of Coimbra

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Ana Agua‐Doce

The Francis Crick Institute

João Eurico Fonseca

University of Lisbon

Rodrigo Pedroso

University of Lisbon

Herman Waldmann

University of Oxford

Annia Pérez‐Riverón

Université de Strasbourg

Saumya Kumar

Centre for Individualised Infection Medicine

José Faro

Universidade de Vigo

Haroon Arshad

Helmholtz Centre for Infection Research

Peggy Riese

Helmholtz Centre for Infection Research

Joana Duarte

Intensive Care Foundation

Cooperative Institutions

University of Lisbon

Helmholtz Centre for Infection Research

Instituto Gulbenkian de Ciência

Medizinische Hochschule Hannover

Centre for Individualised Infection Medicine

Center for Experimental and Clinical Infection Research

Center of Molecular Immunology (Cuba)

Instituto de Medicina Molecular João Lobo Antunes

Hospital de Santa Maria

Centro Hospitalar Lisboa Norte

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Weak euro hits PhDs too

Nature (2000)

Luís Graça Susana Vaz Nery Mónica Bettencourt‐Dias Tiago R. Magalhães

10.1038/35046268

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Modulation of IL-17 and Foxp3 Expression in the Prevention of Autoimmune Arthritis in Mice

PLoS ONE (2010)

Joana Duarte Ana Agua‐Doce Vanessa G. Oliveira João Eurico Fonseca Luís Graça

Background Rheumatoid Arthritis (RA) is a chronic immune mediated disease associated with deregulation of many cell types. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells. Methodology and Findings We investigated whether non-depleting anti-CD4 monoclonal antibodies, which have been reported as pro-tolerogenic, can lead to protection from chronic autoimmune arthritis in SKG mice – a recently described animal model of RA – by influencing the Th17/Treg balance. We found that non-depleting anti-CD4 prevented the onset of chronic autoimmune arthritis in SKG mice. Moreover, treated mice were protected from the induction of arthritis up to 60 days following anti-CD4 treatment, while remaining able to mount CD4-dependent immune responses to unrelated antigens. The antibody treatment also prevented disease progression in arthritic mice, although without leading to remission. Protection from arthritis was associated with an increased ratio of Foxp3, and decreased IL-17 producing T cells in the synovia. In vitro assays under Th17-polarizing conditions showed CD4-blockade prevents Th17 polarization, while favoring Foxp3 induction. Conclusions Non-depleting anti-CD4 can therefore induce long-term protection from chronic autoimmune arthritis in SKG mice through reciprocal changes in the frequency of Treg and Th17 cells in peripheral tissues, thus shifting the balance towards immune tolerance.

Pathogenesis

10.1371/journal.pone.0010558

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Citations (46)

Directed evolution of super-secreted variants from phage-displayed human Interleukin-2

Scientific Reports (2019)

Gertrudis Rojas Tania Carmenate Julio Felipe Santo-Tomás Pedro A. Valiente Marlies Becker

Abstract Selection from a phage display library derived from human Interleukin-2 (IL-2) yielded mutated variants with greatly enhanced display levels of the functional cytokine on filamentous phages. Introduction of a single amino acid replacement selected that way (K35E) increased the secretion levels of IL-2-containing fusion proteins from human transfected host cells up to 20-fold. Super-secreted (K35E) IL-2/Fc is biologically active in vitro and in vivo , has anti-tumor activity and exhibits a remarkable reduction in its aggregation propensity- the major manufacturability issue limiting IL-2 usefulness up to now. Improvement of secretion was also shown for a panel of IL-2-engineered variants with altered receptor binding properties, including a selective agonist and a super agonist that kept their unique properties. Our findings will improve developability of the growing family of IL-2-derived immunotherapeutic agents and could have a broader impact on the engineering of structurally related four-alpha-helix bundle cytokines.

Protein Engineering

10.1038/s41598-018-37280-5

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Citations (14)

Prevention of House Dust Mite Induced Allergic Airways Disease in Mice through Immune Tolerance

PLoS ONE (2011)

Ana Agua‐Doce Luís Graça

Allergic airways disease is a consequence of a Th2 response to an allergen leading to a series of manifestations such as production of allergen-specific IgE, inflammatory infiltrates in the airways, and airway hyper-reactivity (AHR). Several strategies have been reported for tolerance induction to allergens leading to protection from allergic airways disease. We now show that CD4 blockade at the time of house dust mite sensitization induces antigen-specific tolerance in mice. Tolerance induction is robust enough to be effective in pre-sensitized animals, even in those where AHR was pre-established. Tolerant mice are protected from airways eosinophilia, Th2 lung infiltration, and AHR. Furthermore, anti-CD4 treated mice remain immune competent to mount immune responses, including Th2, to unrelated antigens. Our findings, therefore, describe a strategy for tolerance induction potentially applicable to other immunogenic proteins besides allergens.

Pulmonary Eosinophilia

Allergic response

10.1371/journal.pone.0022320

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Systemic dysregulation and molecular insights into poor influenza vaccine response in the aging population

Science Advances (2024)

Saumya Kumar Martijn Zoodsma Nhan Nguyen Rodrigo Pedroso Stephanie Trittel

Vaccination-induced protection against influenza is greatly diminished and increasingly heterogeneous with age. We investigated longitudinally (up to five time points) a cohort of 234 vaccinated >65-year-old vaccinees with adjuvanted vaccine FluAd across two independent seasons. System-level analyses of multiomics datasets measuring six modalities and serological data revealed that poor responders lacked time-dependent changes in response to vaccination as observed in responders, suggestive of systemic dysregulation in poor responders. Multiomics integration revealed key molecules and their likely role in vaccination response. High prevaccination plasma interleukin-15 (IL-15) concentrations negatively associated with antibody production, further supported by experimental validation in mice revealing an IL-15–driven natural killer cell axis explaining the suppressive role in vaccine-induced antibody production as observed in poor responders. We propose a subset of long-chain fatty acids as modulators of persistent inflammation in poor responders. Our findings provide a potential link between low-grade chronic inflammation and poor vaccination response and open avenues for possible pharmacological interventions to enhance vaccine responses.

Vaccine efficacy

10.1126/sciadv.adq7006

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Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation

Scientific Reports (2022)

Filipa Ribeiro Vasco C. Romão Sara Rosa Kátia Jesus Ana Agua‐Doce

Abstract Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto’s thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells ( p = 0.0215) and a reduced Tfr/Tfh ratio ( p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh ( p = 0.0494 and p = 0.0392, respectively) and Tfr ( p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1 + ICOS + Tfh and CD4 + PD-1 + CXCR5 – Tph cells were raised only in patients with SLE ( p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.

CXCR5

Immune Dysregulation

10.1038/s41598-022-21576-8

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T follicular helper and T follicular regulatory cells have different TCR specificity

Nature Communications (2017)

Ana Raquel Maceiras S. C. P. Almeida Encarnita Mariotti‐Ferrandiz Wahiba Chaara Fadi Jebbawi

Abstract Immunization leads to the formation of germinal centres (GCs) that contain both T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Whether T-cell receptor (TCR) specificity defines the differential functions of Tfh and Tfr cells is unclear. Here we show that antigen-specific T cells after immunization are preferentially recruited to the GC to become Tfh cells, but not Tfr cells. Tfh cells, but not Tfr cells, also proliferate efficiently on restimulation with the same immunizing antigen in vitro . Ex vivo TCR repertoire analysis shows that immunization induces oligoclonal expansion of Tfh cells. By contrast, the Tfr pool has a TCR repertoire that more closely resembles that of regulatory T (Treg) cells. Our data thus indicate that the GC Tfh and Tfr pools are generated from distinct TCR repertoires, with Tfh cells expressing antigen-responsive TCRs to promote antibody responses, and Tfr cells expressing potentially autoreactive TCRs to suppress autoimmunity.

10.1038/ncomms15067

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Donor-specific transplantation tolerance: The paradoxical behavior of CD4⁺CD25⁺T cells

Proceedings of the National Academy of Sciences (2004)

Luís Graça Alaín Le Moine Chun‐Yen Lin Paul J. Fairchild Stephen Cobbold

To investigate the antigen specificity of regulatory T cells capable of preventing transplant rejection, we have developed two different strategies to achieve tolerance to fully mismatched skin grafts in euthymic mice. A combination of nondepleting Abs targeting CD4, CD8, and CD154 (CD40 ligand) induces dominant transplantation tolerance to fully mismatched skin allografts. Such tolerance is antigen-specific, mediated by regulatory T cells, and can be extended through linked suppression to naïve lymphocytes. The same protocol, when combined with allogeneic bone marrow, enables the development of mixed hematopoietic chimerism and deletional tolerance. Although we cannot exclude that some regulatory T cells may persist in chimeric mice, these cells are insufficient to mediate linked suppression. CD4 + CD25 + T cells, whether taken from naïve mice or from mice tolerized through either treatment protocol, were always able to prevent rejection of skin grafts by naïve CD4 + T cells, and did so with no demonstrable specificity for the tolerizing donor antigens. Such data question whether CD4 + CD25 + regulatory T cells alone can account for the antigen specificity of dominant transplantation tolerance.

CD154

10.1073/pnas.0400084101

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Citations (109)