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- PD-1 and ICOS are coexpressed in T follicular helper cells but define three stages of maturation of T follicular regulatory cellsPublication . Ribeiro, Filipa; Antunes, Diogo; Pires, Ana R.; Rino, José; Filipe, Beatriz; Jesus, Kátia; Correia, Ricardo; Fonseca, Válter R; Kumar, Saumya; Graca, LuisHumoral responses to infection or vaccination require T cell-B cell interactions. T follicular helper (TFH) cells drive germinal center (GC) responses by providing help to B cells, whereas T follicular regulatory (TFR) cells regulate them. Both mature GC-located TFH and TFR cells are widely characterized by the expression of ICOS and PD-1. However, although human TFR cells share many phenotypic characteristics with TFH cells, we found that ICOS and PD-1 are up-regulated differently in each. Although TFH cells express these proteins synchronously during maturation, they define three maturation stages in TFR cells. TFR cells in an intermediate maturation stage express ICOS, and it is only at the last stage of differentiation that both molecules are expressed at high levels. Although most TFR cells within the B cell follicle are PD-1-, the TFR within the GC are ICOS+PD-1+. These results show that TFH and TFR cells within human lymphoid tissue follow distinct maturation stages.
- Alterations on peripheral blood B-cell subpopulations in very early arthritis patientsPublication . Moura, Rita A.; Weinmann, Pamela; Pereira, Patrícia A.; Caetano-Lopes, Joana; Canhao, Helena; Sousa, Elsa; Mourão, Ana F.; Rodrigues, Ana M.; Queiroz, Mário V.; Souto-Carneiro, Maria M.; Graca, Luis; Fonseca, João EuricoObjective. To characterize circulating B-cell subpopulations of arthritis patients with <6 weeks of disease duration. Methods. Peripheral blood samples were collected from very early untreated polyarthritis patients, with <6 weeks of disease duration, for flow cytometric evaluation of B-cell subpopulations. Samples from patients who were later diagnosed as RA [very early RA (VERA)] were also collected 4–6 weeks after starting a low dose of prednisone (5–10 mg) and 4 months after reaching the minimum effective dose of MTX. A matched healthy group was used as a control. Results. VERA patients have a lower percentage of total peripheral blood memory B cells (CD19+CD27+) and a significant decrease in the frequency of circulating pre-switch memory B cells (CD19+IgD+CD27+) as compared with controls. Therapy with corticosteroids or MTX was unable to restore the normal frequencies of these B-cell subpopulations. A significant decrease in peripheral pre-switch memory B cells is equally observed in other early arthritis patients. Furthermore, no significant differences are found in the frequencies of CD4+ and CD8+ T cells in all patient groups. Conclusions. In very early polyarthritis patients, there is a reduction in circulating pre-switch memory B cells. The reasons that may account for this effect are still unknown. Short-term corticosteroids and MTX do not seem to have a direct effect on circulating B-cell subpopulations in VERA patients.
- T follicular helper and T follicular regulatory cells have different TCR specificityPublication . Maceiras, Ana Raquel; Almeida, Silvia Cristina Paiva; Mariotti-Ferrandiz, Encarnita; Chaara, Wahiba; Jebbawi, Fadi; Six, Adrien; Hori, Shohei; Klatzmann, David; Faro, Jose; Graca, LuisImmunization 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.
- Modulation of IL-17 and Foxp3 expression in the prevention of autoimmune arthritis in micePublication . Duarte, Joana; Agua-Doce, Ana; Oliveira, Vanessa G.; Fonseca, João Eurico; Graca, LuisBackground: 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.
- S100B inhibition protects from chronic experimental autoimmune encephalomyelitisPublication . Barros, Catarina; Barateiro, Andreia; Neto, Alexandre; Soromenho, Beatriz; Basto, Afonso; Mateus, Joana; Xapelli, Sara; Sebastião, Ana M; Brites, Dora; Graca, Luis; Fernandes, AdelaideStudies have correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes occurring in multiple sclerosis. The relevance of S100B in multiple sclerosis pathology brought an emerging curiosity highlighting its use as a potential therapeutic target to reduce damage during the multiple sclerosis course, namely during inflammatory relapses. We examined the relevance of S100B and further investigated the potential of S100B-neutralizing small-molecule pentamidine in chronic experimental autoimmune encephalomyelitis. S100B depletion had beneficial pathological outcomes and based on promising results of a variety of S100B blockade strategies in an ex vivo demyelinating model, we choose pentamidine to assay its role in the in vivo experimental autoimmune encephalomyelitis. We report that pentamidine prevents more aggressive clinical symptoms and improves recovery of chronic experimental autoimmune encephalomyelitis. Blockade of S100B by pentamidine protects against oligodendrogenesis impairment and neuroinflammation by reducing astrocyte reactivity and microglia pro-inflammatory phenotype. Pentamidine also increased regulatory T cell density in the spinal cord suggesting an additional immunomodulatory action. These results showed the relevance of S100B as a main driver of neuroinflammation in experimental autoimmune encephalomyelitis and identified an uncharacterized mode of action of pentamidine, strengthening the possibility to use this drug as an anti-inflammatory and remyelinating therapy for progressive multiple sclerosis.
- Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironmentPublication . Acúrcio, Rita C; Pozzi, Sabina; Carreira, Barbara; Pojo, Marta; Gómez-Cebrián, Nuria; Casimiro, Sandra; Fernandes, Adelaide; Barateiro, Andreia; Farricha, Vitor; Soares Do Brito, Joaquim; Leandro, P; Salvador, Jorge A. R.; Graca, Luis; Puchades-Carrasco, Leonor; Costa, Luis; Satchi-Fainaro, Ronit; Guedes, R. C.; Florindo, Helena FBackground: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.
- Transplantation tolerance: context mattersPublication . Graca, LuisCostimulation blockade has been one of the most studied strategies to achieve immune tolerance, particularly in transplantation. Yet, in spite of the robust nature of the tolerance-inducing potential of costimulation blockade, a comprehensive understanding of the molecular and cellular mechanisms underlying tolerance induction is still missing. Nevertheless, progress has been continuously made. In this issue of the European Journal of Immunology, Chai et al. [Eur. J. Immunol. 2015. 45: 2017-2027] show that transplantation tolerance induced with an anti-CD154 monoclonal antibody relies on the coexistence of several tolerogenic mechanisms rather than one simple regulatory mechanism. These observations highlight the importance of concerted actions involving multiple pathways, namely apoptosis, acquisition of regulatory cells, or inhibition of proliferation, all of which contribute to the induction and maintenance of robust immune tolerance. A better understanding of these distinct tolerogenic pathways may lead to the development of better tolerance-inducing therapeutics.
- Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulationPublication . Ribeiro, Filipa; Romão, Vasco C.; Rosa, Sara; Jesus, Kátia; Agua-Doce, Ana; Barreira, Sofia; Martins, Patrícia; Silva, Susana; Nobre, Ema; Bugalho, Maria João; Fonseca, Valter R; Fonseca, João Eurico; Graca, LuisAutoantibodies 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.
- A Prime-Boost Immunization Strategy with Vaccinia Virus Expressing Novel gp120 Envelope Glycoprotein from a CRF02_AG Isolate Elicits Cross-Clade Tier 2 HIV-1 Neutralizing AntibodiesPublication . Calado, Rita; Duarte, Joana; Borrego, Pedro; Marcelino, José Maria; Bártolo, Inês; Martin, Francisco; Figueiredo, Inês; Almeida, Sílvia; Graça, Luis; Vítor, Jorge M. B.; Silva, Frederico Aires da; Dias, Inês; Carrapiço, Belmira; Taveira, NunoDevelopment of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a truncated version of gp120 (gp120t) from HIV-1 clades CRF02_AG, H, J, B, and C and examined their immunogenicity in mice and rabbits. Mice primed with the recombinant Vaccinia viruses and boosted with the homologous gp120t or C2V3C3 polypeptides developed antibodies that bind potently to homologous and heterologous envelope glycoproteins. Notably, a subset of mice immunized with the CRF02_AG-based envelope immunogens developed a cross-reactive neutralizing response against tier 2 HIV-1 Env-pseudoviruses and primary isolates. Rabbits vaccinated with the CRF02_AG-based envelope immunogens also generated potent binding antibodies, and one animal elicited antibodies that neutralized almost all (13 of 16, 81.3%) tier 2 HIV-1 isolates tested. Overall, the results suggest that the novel CRF02_AG-based envelope immunogens and prime-boost immunization strategy elicit the type of immune responses required for a preventive HIV-1 vaccine.
- T follicular regulatory (Tfr) cells: dissecting the complexity of Tfr‐cell compartmentsPublication . Fonseca, Valter R; Ribeiro, Filipa; Graca, LuisGerminal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody-mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3+ regulatory T cells with unique access to the B-cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody-mediated diseases, and to the identification of novel therapeutic targets.
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