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- Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cellsPublication . Ferreira, Cristina; Barros, Leandro; Baptista, Marta; Blankenhaus, Birte; Barros, André; Figueiredo-Campos, Patricia; Konjar, Spela; Lainé, Alexandra; Kamenjarin, Nadine; Stojanovic, Ana; Cerwenka, Adelheid; Probst, Hans C; Marie, Julien C; Veldhoen, MarcTissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-β8 endows the bioavailability of transforming growth factor-β in the microenvironment, thereby promoting the generation of CD8+ TRM cells.
- Humoral immune response of SARS-CoV-2-infected patients with cancer: influencing factors and mechanismsPublication . Esperança Martins, Miguel; Gonçalves, Lisa; Soares De Pinho, Inês; Gomes, Andreia; Montesinos Serrano, Marta; Blankenhaus, Birte; Figueiredo-Campos, Patricia; Marques, Ana Catarina; Castro-Barbosa, Ana; Cardoso, Ana; Antunes Meireles, Pedro; Atalaia Barbacena, Henrique; Gaspar, Pedro; Howell-Monteiro, Patrícia; Pais-de-Lacerda, António; Mota, Catarina; Veldhoen, MarcBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with cancer show worse outcomes compared with patients without cancer. The humoral immune response (HIR) of patients with cancer against SARS-CoV-2 is not well characterized. To better understand it, we conducted a serological study of hospitalized patients with cancer infected with SARS-CoV-2. Materials and methods: This was a unicentric, retrospective study enrolling adult patients with SARS-CoV-2 admitted to a central hospital from March 15 to June 17, 2020, whose serum samples were quantified for anti-SARS-CoV-2 receptor-binding domain or spike protein IgM, IgG, and IgA antibodies. The aims of the study were to assess the HIR to SARS-CoV-2; correlate it with different cancer types, stages, and treatments; clarify the interplay between the HIR and clinical outcomes of patients with cancer; and compare the HIR of SARS-CoV-2-infected patients with and without cancer. Results: We included 72 SARS-CoV-2-positive subjects (19 with cancer, 53 controls). About 90% of controls revealed a robust serological response. Among patients with cancer, a strong response was verified in 57.9%, with 42.1% showing a persistently weak response. Treatment with chemotherapy within 14 days before positivity was the only factor statistically shown to be associated with persistently weak serological responses among patients with cancer. No significant differences in outcomes were observed between patients with strong and weak responses. All IgG, IgM, IgA, and total Ig antibody titers were significantly lower in patients with cancer compared with those without. Conclusion: A significant portion of patients with cancer develop a proper HIR. Recent chemotherapy treatment may be associated with weak serological responses among patients with cancer. Patients with cancer have a weaker SARS-CoV-2 antibody response compared with those without cancer. Implications for practice: These results place the spotlight on patients with cancer, particularly those actively treated with chemotherapy. These patients may potentially be more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, so it is important to provide oncologists further theoretical support (with concrete examples and respective mechanistic correlations) for the decision of starting, maintaining, or stopping antineoplastic treatments (particularly chemotherapy) not only on noninfected but also on infected patients with cancer in accordance with cancer type, stage and prognosis, treatment agents, treatment setting, and SARS-CoV-2 infection risks.
- Eimeria vermiformis Infection model of Murine small intestinePublication . Figueiredo-Campos, Patricia; Ferreira, Cristina; Blankenhaus, Birte; Veldhoen, MarcEimeria vermiformis is a tissue specific, intracellular protozoan that infects the murine small intestinal epithelia, which has been widely used as a coccidian model to study mucosal immunology. This mouse infection model is valuable to investigate the mechanisms of host protection against primary and secondary infection in the small intestine. Here, we describe the generation of an E. vermiformis stock solution, preparation of sporulated E. vermiformis to infect mice and determination of oocysts burden. This protocol should help to establish a highly reproducible natural infection challenge model to study immunity in the small intestine. The information obtained from using this mouse model can reveal fundamental mechanisms of interaction between the pathogen and the immune response, e.g., provided by intraepithelial lymphocytes (IEL) at the basolateral site of epithelial cells but also a variety of other immune cell populations present in the gut.
- Intestinal tissue-resident T cell activation depends on metabolite availabilityPublication . Konjar, Spela; Ferreira, Cristina; Carvalho, Filipa; Figueiredo-Campos, Patricia; Fanczal, Júlia; Ribeiro, Sofia; Morais, Vanessa A.; Veldhoen, MarcThe metabolic capacity of many cells is tightly regulated and can adapt to changes in metabolic resources according to environmental changes. Tissue-resident memory (TRM) CD8+ T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. TRM cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier. In the small intestine, the types of TRM cells are intraepithelial lymphocytes (IELs), which contain high levels of cytotoxic molecules and express activation markers, suggesting a heightened state of activation. We hypothesize that the tissue environment may determine IEL activity. We show that IEL activation, in line with its semiactive status, is metabolically faster than circulating CD8+ T cells. IEL glycolysis and oxidative phosphorylation (OXPHOS) are interdependently regulated and are dependent on rapid access to metabolites from the environment. IELs are restrained by local availability of metabolites, but, especially, glucose levels determine their activity. Importantly, this enables functional control of intestinal TRM cells by metabolic means within the fragile environment of the intestinal epithelial barrier.
- Seroprevalence of anti‐SARS‐CoV‐2 antibodies in COVID‐19 patients and healthy volunteers up to 6 months post disease onsetPublication . Figueiredo-Campos, Patricia; Blankenhaus, Birte; Mota, Catarina; Gomes, Andreia; Serrano, Marta; Ariotti, Silvia; Costa, Catarina; Nunes-Cabaço, Helena; Mendes, António M.; Gaspar, Pedro; Pereira‐Santos, M. Conceição; Rodrigues, Fabiana; Condeço, Jorge; Escoval, M. Antonia; Santos, Matilde; Ramirez, Mário; Cristino, José Melo; Simas, J Pedro; Vasconcelos, Eugenia; Afonso, Ângela; Veldhoen, MarcSARS-CoV-2 has emerged as a human pathogen, causing clinical signs, from fever to pneumonia-COVID-19-but may remain mild or asymptomatic. To understand the continuing spread of the virus, to detect those who are and were infected, and to follow the immune response longitudinally, reliable and robust assays for SARS-CoV-2 detection and immunological monitoring are needed. We quantified IgM, IgG, and IgA antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein over a period of 6 months following COVID-19 onset. We report the detailed setup to monitor the humoral immune response from over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff, and 198 post-COVID-19 volunteers. Anti-SARS-CoV-2 antibody responses follow a classic pattern with a rapid increase within the first three weeks after symptoms. Although titres reduce subsequently, the ability to detect anti-SARS-CoV-2 IgG antibodies remained robust with confirmed neutralization activity for up to 6 months in a large proportion of previously virus-positive screened subjects. Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Importantly, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2.
- Immune-microbe crosstalk : modulation of adaptive immune system by the microbiota and SARS-CoV2Publication . Figueiredo-Campos, Patricia; Veldhoen, MarcAdaptive immune responses are supported by lymphocytes that are broadly divided into B and T cells, which provide antibody and cell-mediated immune responses, respectively. Adaptive immunity is characterized by a specific pathogen recognition, generation of memory, and regulation of homeostasis. Lymphocytes develop and are activated in the lymphoid organs and can also re-circulate within the tissues. Intestinal Intraepithelial lymphocytes (IELs) occupy the top layers of epithelial barriers and are broadly composed of natural IELs (CD8ααTCRγδ) and induced IELs (CD8αβTCRαβ and CD4TCRαβ). IELs are kept in a heightened but controlled state of activation, have reciprocal interactions with the intestinal epithelial cells (IECs) and microbiota. There is evidence supporting that IELs contribute to the pathogenesis of gut disorders such as celiac disease and inflammatory bowel disease (IBD). Yet, the stimuli that control IELs activity and the molecular pathways involved remain unclear. In the context of a parasite infection, caused by Eimeria vermiformis that infects mouse IECs, induced IELs but not natural IELs are strongly activated. Interestingly, upon treatment with broad-spectrum antibiotics, followed by E.vermiformis infection, natural IELs proliferation is boosted. This proliferation boost is traced to Grampositive bacteria, the major producers of short-chain fatty acids (SCFA) and lactate. The hyperproliferative phenotype was also observed in the context of antibiotics and Dextran Sulphate Sodium (DSS) treatment. However, here just natural IELs got activated and induced IELs were not affected by the treatment. Importantly, the IEL proliferation boost is reversed by faecal microbiota transplantation (FMT) under antibiotics treatment and infection compared with no FMT. IELs do not express SCFA receptors but glucagon-like peptide-1 receptor (GLP-1R) is highly expressed by them. Fatty acid and lactate receptors are expressed by intestinal enteroendocrine L cells that produce GLP-1. Interestingly, we found GLP-1 mRNA and serum levels increased upon antibiotics treatment and DSS or E.vermiformis infection. Moreover, administration of Ex-9, a GLP-1 antagonist, reduced natural IELs proliferation. A diverse microbiota composition is important to sustain IELs and maintain their semi-activated state without effector function. Upon bacterial dysbiosis, especially reduced Gram-positives, natural IELs proliferation is released, and GLP-1 levels are increased. Currently, we characterise the microbiota complexity via 16S rRNA sequencing to understand the community that is responsible for keeping the natural IELs at the quiet state of activation. In the absence of this community, natural IELs proliferation is released, which could lead to gut inflammation, such as seen in IBD. Therefore, by manipulating the microbiota composition, the importance of specific bacteria and/or bacterial products that influence natural IELs activation and function will be addressed. This way, it will be possible to control the proliferation and activation of these cells to restore gut homeostasis. On December 2019 a novel virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified from an outbreak in Wuhan, China, being responsible for the COVID-19 pandemic. In Portugal, the first case was reported in March 2020. In April 2020, we started working to understand the spreading of the virus, to identify those who are and were infected, and to follow the immune response longitudinally. We created a reliable and robust assay for SARS-CoV-2 detection and immunological monitoring. We designed an Enzyme linked immunosorbent assay (ELISA) assay to quantify IgM, IgG, and IgA antibodies against SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein. We described the meticulous setup to monitor the humoral immune response of over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff, and 198 post-COVID-19 volunteers. SARS-CoV-2 infection induced a classic pattern of antibody responses with a rapid increase within the first three weeks after symptoms. Anti-SARS-CoV-2 IgG antibodies reduced in titres, although remaining robust with confirmed neutralization activity for up to 6 months in a large proportion of previously virus-positive screened individuals. Our work provides detailed information for the assays used, facilitating longitudinal analysis of protective immunity to SARS-CoV-2. Importantly, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2.