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The use of ionising radiation (IR) for medical diagnosis and treatment procedures has had a major impact on the survival of paediatric patients. Although the benefits of these techniques lead to efficient health care, evaluation of potential associated long-term health effects is required. HARMONIC aims to better understand the increased risk of cancer and non-cancer effects after exposure to medical IR in children with cancer treated with modern external beam radiotherapy (EBRT) – radiation energy in MeV range – and in children with cardiac defects diagnosed and treated with cardiac fluoroscopy procedures (CFP) – radiation energy in keV range. The project investigates, among survivors of paediatric cancer, potential endocrine dysfunction, cardiovascular and neurovascular damage, health-related quality of life and second (and subsequent) primary cancer (SPC). The cardiac component builds a pooled cohort of approximately 90 000 paediatric patients who underwent CFP during childhood and adolescence to investigate cancer risk following exposure to IR and explore the potential effects of conditions predisposing to cancer. HARMONIC develops software tools to allow dose reconstruction in both EBRT and CFP to enable epidemiological investigations and future optimisation of treatments. With the creation of a biobank of blood and saliva samples, HARMONIC aims to provide a mechanistic understanding of radiation-induced adverse health effects and identify potential biomarkers that can predict these effects.

Additional support from ISGlobal’s Antoni Plasència and Josep M. Antó, Circulation of the Omicron BA.5 subvariant has led to a considerable increase in cases and also in hospitalisations (but not severe cases or deaths) in recent weeks in Catalonia, the rest of Spain and many other countries. Based on scientific evidence and the current epidemiological situation, the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC) has conducted an analysis of the impact of the BA-5 subvariant in Catalonia and, with the support of the COVID-19 Scientific Advisory Committee (CCAC) attached to the Department of Health of the Government of Catalonia, has issued a series of recommendations for booster vaccination strategies.

Additional support from ISGlobal’s Antoni Plasència and Josep M. Antó, A variety of studies suggest that up to 10-15% of all patients with COVID-19 may present persistent symptomatology weeks or even months after the original infection. Given the accumulated burden of COVID-19 in Catalonia, Spain, we speculate that over 90,000 patients could have been or are currently affected by persistent symptoms or sequelae. The Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC) presents its third report where they propose a clear set of case definitions of Post-Acute COVID syndrome (PACS) and its sub-categories and recommend a comprehensive medical examination to characterise the clinical features and complications when assessing PACS.

Background Malaria diagnosis in many malaria-endemic countries relies mainly on the use of rapid diagnostic tests (RDTs). The majority of commercial RDTs used in Africa detect the Plasmodium falciparum histidine-rich protein 2 (PfHRP2). pfhrp2/3 gene deletions can therefore lead to false-negative RDT results. This study aimed to evaluate the frequency of PCR-confirmed, false-negative P. falciparum RDT results in Monrovia, Liberia. Methods PfHRP2-based RDT (Paracheck Pf®) and microscopy results from 1038 individuals with fever or history of fever (n = 951) and pregnant women at first antenatal care (ANC) visit (n = 87) enrolled in the Saint Joseph’s Catholic Hospital (Monrovia) from March to July 2019 were used to assess the frequency of false-negative RDT results. True–false negatives were confirmed by detecting the presence of P. falciparum DNA by quantitative PCR in samples from individuals with discrepant RDT and microscopy results. Samples that were positive by 18S rRNA qPCR but negative by PfHRP2-RDT were subjected to multiplex qPCR assay for detection of pfhrp2 and pfhrp3. Results One-hundred and eighty-six (19.6%) and 200 (21.0%) of the 951 febrile participants had a P. falciparum-positive result by RDT and microscopy, respectively. Positivity rate increased with age and the reporting of joint pain, chills and shivers, vomiting and weakness, and decreased with the presence of coughs and nausea. The positivity rate at first ANC visit was 5.7% (n = 5) and 8% (n = 7) by RDT and microscopy, respectively. Out of 207 Plasmodium infections detected by microscopy, 22 (11%) were negative by RDT. qPCR confirmed absence of P. falciparum DNA in the 16 RDT-negative but microscopy-positive samples which were available for molecular testing. Among the 14 samples that were positive by qPCR but negative by RDT and microscopy, 3 only amplified pfldh, and among these 3 all were positive for pfhrp2 and pfhrp3. Conclusion There is no qPCR-confirmed evidence of false-negative RDT results due to pfhrp2/pfhrp3 deletions in this study conducted in Monrovia (Liberia). This indicates that these deletions are not expected to affect the performance of PfHRP2-based RDTs for the diagnosis of malaria in Liberia. Nevertheless, active surveillance for the emergence of PfHRP2 deletions is required.

Background: Malaria diagnosis relies mainly on the use of rapid diagnostic tests (RDTs). The majority of commercial RDTs used in Africa detect the Plasmodium falciparum histidine-rich protein 2 (PfHRP2). pfhrp2/3 gene deletions can therefore lead to false-negative RDT results. This study aimed to evaluate the frequency of PCR-confirmed, false-negative P. falciparum RDT results in Monrovia, Liberia.Methods: We used PfHRP2-based RDT (Paracheck Pf®) and microscopy results from 1038 individuals with fever or history of fever (n=951) and pregnant women at first antenatal care (ANC) visit (n=87) enrolled in the Saint Joseph Catholic Hospital (Monrovia) from March to July 2019 to assess the frequency of false-negative RDT results. True false negatives were confirmed by detecting the presence of P. falciparum DNA by quantitative PCR in samples from individuals with discrepant RDT and microscopy resultsResults: One hundred and eighty-six (19.6%) and 200 (21.0%) of the 951 febrile participants had a P. falciparum positive result by RDT and microscopy, respectively. Positivity rate increased with age and the reporting of joint pain, chills and shivers, vomiting and weakness, and increased with the presence of coughs and nausea. The positivity rate at first ANC visit was 5.7% (n=5) and 8% (n=7) by RDT and microscopy, respectively. Out of 207 Plasmodium infections detected by microscopy, 22 (11%) were negative by RDT. qPCR confirmed absence of P. falciparum DNA in the sixteen RDT-negative but microscopy-positive samples which were available for molecular testing. Conclusion: There is no qPCR-confirmed evidence of false-negative RDT results due to pfhrp2/pfhrp3 deletions in this study conducted in Monrovia (Liberia). This indicates the appropriate performance of PfHRP2-based RDTs for the diagnosis of malaria in Liberia. Nevertheless, active surveillance for the emergence of PfHRP2 deletions is required.

This paper, the last in the Special Issue (SI) on the SHAMISEN project, presents an overview of the SHAMISEN Recommendations for Preparedness and Health Surveillance of Populations Affected by a Radiation Accident. The recommendations are based on the lessons learnt from previous nuclear accidents, and the engagement activities with different stakeholder groups, described in the other papers of this SI. The SHAMISEN project developed a total of 28 recommendations. They include general recommendations, applicable across all phases of an accident, and specific recommendations for each of the three main phases: preparedness, early and intermediate, and long-term recovery. The recommendations are subdivided by topic: health surveillance, epidemiological studies, dose reconstruction, evacuation, and training of and communication with health personnel and other actors involved in liaising with affected populations. Each recommendation is divided into 3 sections - why, how and who - thus providing background and concrete advice as to how each SHAMISEN recommendation should be implemented and by whom. It is notable that many recommendations are also applicable to other disaster types, including the current SARS-CoV-2 pandemic. SHAMISEN was supported by the EURATOM (European Atomic Energy Community) program of the European Commission in the framework of the OPERRA (Open Project for the European Radiation Research Area) project (FP7 grant agreement No. 604984).

Mexico is the center of domestication and a center for diversity of maize. Area planted with maize is the country’s largest agricultural land use, mostly planted by smallholder family farmers known as campesinos. Due to the large area they plant with saved seed from native varieties in a wide variety of environments across the country, maize evolution under domestication continues today at a very large scale and under a multiplicity of selection pressures. Campesinos have been considered mainly subsistence farmers. Here we show that subsistence production is insufficient for explaining the scale of the area they plant with maize and on which its contemporary evolution under domestication depends. Our hypothesis is that beyond supplying their own consumption needs, campesinos across Mexico collectively produce maize to respond to the demand of non-maize producing local consumers. Here we quantify the extent of subsistence versus surplus production among campesinos, showing that subsistence production cannot explain the scale of their maize cultivation. Then, we test statistically the association between the scale of maize cultivation and socioeconomic variables that link campesino production to the demand by other consumers and examine the implications of the results for the supply and conservation of native maize in the country. Our results suggest that maize trading linking campesinos to other consumers may be important and widespread. We conclude that there are important opportunities for maintaining maize evolution under domestication at large scale by strengthening local maize markets.

Emergency preparedness and response (EP&R) to radiological or nuclear accidents depends on many different stakeholder groups: nuclear and radiological regulators and authorities; institutions and ministries concerned by health, environment and consumption; first-line responders including the police, military, firefighters and health workers; as well as local authorities and nuclear industries. Stakeholders also include the general public, such as people living near NPPs8 or affected by previous nuclear or radiological accidents and incidents. Teachers and journalists, bloggers and other social media figures would play a key role in effective dissemination of knowledge and information. NGOs9 or civil associations/societies can also be involved in radiation monitoring and protection. The present study describes the role of different research institutions (such as CIEMAT10, UPM11 and ISGlobal12) and of the Spanish Society of Radiological Protection (SEPR) in bringing together the above-listed stakeholders in Spain to discuss EP&R and identify benefits and challenges of working together. Stakeholder opinions on EP&R, collected mainly in the framework of several European-funded projects, are provided. Remaining barriers and examples of good practices in radiation protection are discussed, as well as recommendations for improving nuclear and radiological emergency preparedness in Spain. The conclusions may be useful for other countries. Funded under H2020 EJP CONCERT_JTC2016, GA 662287, under FP7-EURATOM-FISSION, GA 269718, under FP7-EURATOM-FISSION, GA 323287 and under FP6-EURATOM-RADPROT, contract No. FI6R-CT- 2004-508843

Efficient priming of anti-tumor T cells requires the uptake and presentation of tumor antigens by immunogenic dendritic cells (DCs) and occurs mainly in lymph nodes draining the tumor (tdLNs). However, tumors expand and activate myeloid-derived suppressor cells (MDSCs) that inhibit CTL functions by several mechanisms. While the immune-suppressive nature of the tumor microenvironment is largely documented, it is not known whether similar immune-suppressive mechanisms operate in the tdLNs. In this study, we analyzed MDSC characteristics within tdLNs. We show that, in a metastasis-free context, MO-MDSCs are the dominant MDSC population within tdLNs, that they are highly suppressive and that tumor proximity enhances their recruitment to tdLN via a CCR2/CCL2-dependent pathway. Altogether our results uncover a mechanism by which tumors evade the immune system that involves MDSC-mediated recruitment to the tdLN and the inhibition of T-cell activation even before reaching the highly immunosuppressive tumor microenvironment.

Experience suggests that current nuclear accident response planning in European countries mostly has a technical focus, with less attention paid to social, psychological and ethical issues. Information provided tends to be directed towards decisions made by experts, rather than for the support of affected populations. The SHAMISEN (Nuclear Emergency Situations - Improvement of Medical And Health Surveillance) consortium, composed of close to 50 experts from 10 countries, performed a critical review of current recommendations and experiences regarding dose assessment and reconstruction, evacuation decisions, long-term health surveillance programmes and epidemiological studies. The review included case studies and lessons drawn from the living conditions and health status of populations affected by the Chernobyl and Fukushima accidents, taking an integrative approach to health and well-being. Based on this work, SHAMISEN developed a series of comprehensive recommendations aimed at improving the preparedness, response, long-term surveillance and living conditions of populations affected by past or future radiation accidents, in a manner responding to their needs, while minimising unnecessary anxiety. The SHAMISEN project was supported by the EURATOM (European Atomic Energy Community) programme of the European Commission in the framework of the OPERRA (Open Project for the European Radiation Research Area) project (FP7 grant agreement No. 604984). ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Programme (http://cerca.cat/en/). NMBU acknowledges the support of the Research Council of Norway, Grant No. 263856.

Additional file 1. Program of the GCLP Workshop.

Additional file 4. Pre- and post-training questionnaire.

Additional file 2. Program of the SOP Workshop.

Background Limited health research capacities (HRC) undermine a country’s ability to identify and adequately respond to local health needs. Although numerous interventions to strengthen HRC have been conducted in Africa, there is a need to share the lessons learnt by funding organizations, institutes and researchers. The aim of this report is to identify best practices in HRC strengthening by describing a training programme conducted between 2016 and 2017 at the Saint Joseph’s Catholic Hospital (SJCH) in Monrovia (Liberia). Methods A call for trainees was launched at the SJCH, the Liberia Medicines and Health Products Regulatory Authority (LMHRA), the Ministry of Health and Social Welfare, the Mother Pattern College of Health Sciences (MPCHS) and community members. Selected trainees participated in four workshops on Good Clinical Laboratory Practice (GCLP), standard operating procedures (SOP) and scientific communication, as well as in a 5-months eLearning mentoring programme. After the training, a collectively-designed research project on malaria was conducted. Results Twenty-one of the 28 trainees (14 from the SJCH, 3 from LMHRA, one from MPCHS, and 10 community representatives) completed the programme satisfactorily. Pre- and post-training questionnaires completed by 9 of the trainees showed a 14% increase in the percentage of correct answers. Trainees participated in a mixed-methods cross-sectional study of Plasmodium falciparum infection among pregnant women at the SJCH. Selected trainees disseminated activities and research outcomes in three international meetings and three scientific publications. Conclusion This training-through-research programme successfully involved SJCH staff and community members in a practical research exercise on malaria during pregnancy. The challenge is to ensure that the SJCH remains active in research. Harmonization of effectiveness indicators for HRC initiatives would strengthen the case for investing in such efforts. Electronic supplementary material The online version of this article (10.1186/s12936-019-2767-1) contains supplementary material, which is available to authorized users.

Additional file 3. Program of the Workshop in scientific writing.

Background: Liberia is a West African country that needs substantial investment to strengthen its National Malaria Control Programme (NMCP), which was disrupted during the 2014–2016 Ebola epidemic. As elsewhere, Liberian pregnant women are especially vulnerable to malaria. Understanding prevention and treatment-seeking behaviours among the population is crucial to strategize context-specifc and women-centred actions, including locally-led malaria research, to improve women’s demand, access and use of NMCP strategies against malaria in pregnancy. Methods: In 2016, after the Ebola crisis, a qualitative inquiry was conducted in Monrovia to explore populations’ insights on the aetiology, prevention and therapeutics of malaria, as well as the community and health workers’ perceptions on the utility of malaria research for pregnant women. In-depth interviews and focus group discussions were conducted among pregnant women, traditional community representatives and hospital staf (n=38), using a feminist interpretation of grounded theory. Results: The narratives indicate that some Liberians believed in elements other than mosquito bites as causes of malaria; many had a low malaria risk perception and disliked current efective prevention methods, such as insecticide-treated nets; and some would resort to traditional medicine and spiritual care to cure malaria. Access to clinic-based malaria care for pregnant women was reportedly hindered by lack of fnancial means, by unofcial user fees requested by healthcare workers, and by male partners’ preference for traditional medicine. The participants suggested that malaria research in Liberia could help to design evidence-based education to change current malaria prevention, diagnostic and treatment-seeking attitudes, and to develop more acceptable prevention technologies. Conclusion: Poverty, insufcient education on malaria, corruption, and poor trust in healthcare establishment are structural factors that may play a greater role than local traditional beliefs in deterring Liberians from seeking, access‑ ing and using government-endorsed malaria control strategies. To increase access to and uptake of preventive and biomedical care by pregnant women, future malaria research must be informed by people’s expressed needs and constructed meanings and values on health, ill health and healthcare.

BACKGROUND: Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials. In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria. Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population. However, pregnant women are especially vulnerable when targeted as research participants. Whilst some studies in the region attempted to understand the ethical issues around the conduct of clinical research, there is need of such information from Liberia to inform future malaria research. METHODS: This is a grounded theory study that aims to understand the barriers and opportunities for pregnant women to consent to participate in malaria research in Liberia. The study was conducted between November 2016 and May 2017 at the St Joseph's Catholic Hospital, Monrovia. In-depth interviews and focus group discussions were held with hospital staff, traditional community representatives, and pregnant women. RESULTS: According to the participants, useful strategies to motivate pregnant women to consent to participate in malaria research could be providing evidence-based education on malaria and research to the general population and encouraging engagement of traditional leaders in research design and community mobilization. Fears and suspicions towards research and researchers, which were amplified during the conduct of Ebola vaccine and drug clinical trials, may influence women's acceptance and willingness to engage in malaria research. Population's mistrust in the public healthcare system might hinder their acceptance of research, undermining the probability of their benefiting from any improved malaria control intervention. CONCLUSION: Benchmarking for acceptable practices from previous public health interventions; building community discussion and dissemination platforms; and mapping communication and information errors from how previous research interventions were explained to the Liberian population, are strategies that might help ensure a safe and fully informed participation of pregnant women in malaria research. Inequity issues impeding access and use of biomedical care for women must be tackled urgently.

The atypical chemokine receptor D6 is a decoy and scavenger receptor for most inflammatory CC chemokines and prevents the development of exacerbated inflammatory reactions. Here we report that mice lacking D6 expression in the nonhematopoietic compartment have a selective increase in the number of Ly6Chigh monocytes in the circulation and in secondary lymphoid tissues. Under inflammatory conditions, Ly6Chigh monocytes accumulate in increased number in secondary lymphoid organs of D6−/− mice in a CCR2-dependent manner. Ly6Chigh monocytes derived from D6−/− mice have enhanced immunosuppressive activity, inhibit the development of adaptive immune responses, and partially protect mice from the development of GVHD. Thus, control of CCR2 ligands by D6 regulates the traffic of Ly6Chigh monocytes and controls their immunosuppressive potential.

CD5 was one of the first surface receptors described for mouse and human T lymphocytes. Since then, it has been found to be highly expressed by regulatory T cells and a subpopulation of regulatory B cells, to be physically associated with the T- and B-cell antigen receptors, to negatively modulate TCR- and BCR-mediated signals, and to bind certain pathogen-associated molecular patterns. These findings position CD5 as an attractive target for developing immunotherapies aimed at either boosting or dampening ongoing immune responses. Here the available data on the function of CD5 and its involvement in the regulation of immune responses in health and disease are reviewed, as well as the evidence for and future challenges in developing therapeutic strategies aimed at targeting CD5 for autoimmune diseases, cancer, and infections.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.

Orta-Mascaró et al., The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALC AM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6-/- thymi showed a reduction in both CD4 and CD8 single-positive subsets, and double-positive thymocytes exhibited increased Ca2 mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell-autonomous selective disadvantage of CD6-/- T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6-/- mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4TEM and CD8TCM) and regulatory (T reg) T cells. The suppressive activity of CD6-/- T reg cells was diminished, and CD6-/- mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells., This work is supported by grants from: Worldwide Cancer Research (14-1275) and Fundació La Marató TV3 (201319-30) to F. Lozano; Spanish Ministerio de Economía y Competitividad (Plan Nacional I+D+i) co-financed by European Development Regional Fund “A way to achieve Europe” to F. Lozano (SAF2013-46151-R), J. Merino (SAF2012-34059), R. Merino (SAF2014-55088-R), and R. Vicente (SAF2014- 52228-R); IPT2011-1527-010000 (associated to Fibrostatin SL) to J. Merino; and Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, European Research Council (FP7/2007–2013 grant no. 322465), and ANR grant Basilic to B. Malissen and M. Malissen. M. Orta-Mascaró, I. Simões, and E. Carreras are recipients of fellowships from Ministerio de Economía y Competitividad (BES-2011-048415), Fundação para a Ciência e a Tecnologia (SFRH/ BD/75738/2011), and European Community Seventh Framework Program (BIOTRACK, FP7/2007/2013;229673), respectively. National Institutes of Health grants to Velocigene at Regeneron Inc. (U01HG004085), and the CSD Consortium (U01HG004080) funded the generation of gene-targeted vectors and ES cells for 8,500 genes in the KOMP Program and archived and distributed by the KOMP Repository at UC Davis and CHORI (U42RR024244).

Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune-mediated rejection of cancer.

Two new studies in mice, published in Science, show that the commensal bacteria populations in the gut play a key role in boosting responses to different antitumor regimens. These results argue for a rational use of antibiotics when managing infections in patients undergoing cancer therapies.

The molecular signals involved in the generation of thymic regulatory T cells (Treg) still remain controversial. It has been proposed that high avidity interactions are required for Treg selection. Here, we used double transgenic mice (TCR-HA x IgHA) and followed the kinetics and phosphorylation status of HA-specific Tregs that develop in the absence or presence of their agonist ligand expressed in the thymus, as well as of polyclonal "naturally occurring" Tregs (nTregs). We found that, in basal conditions, nTregs showed enhanced basal phosphorylation of c-Cbl, Erk and PI3K, indicating their selection by high avidity ligands. However, in response to TCR cross-linking, both nTregs from Balb/c mice and HA-specific Tregs showed reduced levels of phosphorylated Erk1/2, c-Cbl and Akt. We conclude that thymus-derived Tregs display a characteristic "signalling signature" that suggests qualitative differences in TCR-mediated signalling that may not be explained merely by a higher TCR avidity.

It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of “naturally occurring” CD4+CD25+ Treg (nTreg). Analysis of CD5−/− mice showed a significant increase in the percentage and absolute numbers of CD4+ CD25+Foxp3+ thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5−/− mice showed reduced cellularity due to increased apoptosis, which preferentially affected naive T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5−/− nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5−/− naive T cells but not CD5−/− nTreg showed lower levels of p-Akt. Finally, CD5−/− nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4+CD25− naive thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.

Establishment of cell–cell adhesion is crucial in embryonic development as well as within the stem cell niches of an adult. Adhesion between macrophages and erythroblasts is required for the formation of erythroblastic islands, specialized niches where erythroblasts proliferate and differentiate to produce red blood cells throughout life. The Eph family is the largest known family of receptor tyrosine kinases (RTKs) and controls cell adhesion, migration, invasion and morphology by modulating integrin and adhesion molecule activity and by modifying the actin cytoskeleton. Here, we identify the proteoglycan agrin as a novel regulator of Eph receptor signaling and characterize a novel mechanism controlling cell–cell adhesion and red cell development within the erythroid niche. We demonstrate that agrin induces clustering and activation of EphB1 receptors on developing erythroblasts, leading to the activation of α5β1 integrins. In agreement, agrin knockout mice display severe anemia owing to defective adhesion to macrophages and impaired maturation of erythroid cells. These results position agrin-EphB1 as a novel key signaling couple regulating cell adhesion and erythropoiesis.

Mesenchymal stem cells (MSCs; also called mesenchymal stromal cells) have received much attention during the last two decades, at first because of their regeneration capacity and poor immunogenicity and, more recently, because of their proved immunomodulatory function. Consequently, the number of studies addressing MSC biology and their capacity to treat a broad range of human diseases at the preclinical and clinical level has grown exponentially, with often confusing and conflicting results. The use of poorly defined cell preparations and experimental models, many of them in vitro, has added to such confusion. In this review, we identify what in our opinion remain the main open questions on MSC biology and we attempt to distinguish the facts from the myths concerning endogenous and therapeutic MSC.

Mesenchymal stem cells (MSCs) are self-renewable, multipotent progenitor cells able to differentiate into various mesodermal lineages.1 MSCs are present in basically all tissues, and have a pivotal role in tissue repair and in local control of inflammation.

WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a rare disease characterized by diverse symptoms indicative of aberrantly functioning immunity. It is caused by mutations in the chemokine receptor CXCR4, which impair its intracellular trafficking, leading to increased responsiveness to chemokine ligand and retention of neutrophils in bone marrow. Yet WHIM symptoms related to adaptive immunity, such as delayed IgG switching and impaired memory B-cell function, remain largely unexplained. We hypothesized that the WHIM-associated mutations in CXCR4 may affect the formation of immunologic synapses between T cells and antigen-presenting cells (APCs). We show that, in the presence of competing external chemokine signals, the stability of T-APC conjugates from patients with WHIM-mutant CXCR4 is disrupted as a result of impaired recruitment of the mutant receptor to the immunologic synapse. Using retrogenic mice that develop WHIM-mutant T cells, we show that WHIM-mutant CXCR4 inhibits the formation of long-lasting T-APC interactions in ex vivo lymph node slice time-lapse microscopy. These findings demonstrate that chemokine receptors can affect T-APC synapse stability and allow us to propose a novel mechanism that contributes to the adaptive immune response defects in WHIM patients.

It has been suggested, but not formally demonstrated, that peripheral dendritic cells (DC) alone are capable of tolerance induction by clonal deletion and/or anergy. To resolve such an issue, it is important to develop in vivo systems where DC are the only cells capable of presenting antigen and where a T cell population with a known antigen specificity can be followed. Here we use a transgenic murine model, which expresses the influenza virus hemagglutinin (HA) on B cells and on CD8alpha(+) and CD8alpha(-) DC but not on macrophages. If these mice are on a RAG(-/-) background, one has a model in which only DC present the HA antigen. In these mice, HA-specific T cells are deleted very efficiently in the thymus and those remaining in the periphery cannot respond to further antigenic stimulation in vitro and cannot eliminate antigen in vivo. By performing adoptive transfers, we show for the first time that self-antigen presentation exclusively by peripheral DC results in very efficient clonal deletion of the majority of antigen-specific T cells with the remaining ones in an anergic state. This model will permit us to further address the mechanisms by which DC tolerize or prime T cells and to investigate whether anergy induction by DC is similar to anergy induction by B cells.

CD6, one of the first antigens to be identified on T cells, is a membrane glycoprotein that physically associates with the antigen receptor complex. Because of this, its main function seems to involve the modulation of TCR-mediated signaling pathways. However, growing evidence indicates that this ancient and conserved scavenger-like receptor may also play a role as pattern recognition receptor (PRR), similar to other members of the scavenger receptor cysteine rich superfamily (SRCR-SF). Here, we discuss the functional interactions of CD6 with microbe- and damage-associated signals and the potential use of soluble forms of CD6 in the therapeutic treatment of bacterial infections, in particular multi-drug resistant bacterial strains. Importantly, microbe recognition by CD6 may also have functional consequences on T cell activation and differentiation, which remain to be explored.

Organization of immune responses requires exchange of information between cells. This is achieved through either direct cell–cell contacts and establishment of temporary synapses or the release of soluble factors, such as cytokines and chemokines. Here we show a novel form of cell-to-cell communication based on adenosine triphosphate (ATP). ATP released by stimulated T cells induces P2X4/P2X7-mediated calcium waves in the neighboring lymphocytes. Our data obtained in lymph node slices suggest that, during T-cell priming, ATP acts as a paracrine messenger to reduce the motility of lymphocytes and that this may be relevant to allow optimal tissue scanning by T cells.

Two new studies in mice, published in Science, show that the commensal bacteria populations in the gut play a key role in boosting responses to different antitumor regimens. These results argue for a rational use of antibiotics when managing infections in patients undergoing cancer therapies.

Peripheral T cell tolerance may result from activation-induced cell death [1], anergy [1], and/or immune response modulation by regulatory T cells [2] . In mice that express a transgenic receptor specific for peptide 111–119 of influenza hemagglutinin presented by E d class II MHC molecules as well as hemagglutinin under control of the immunoglobulin-κ promoter, we have found that anergic T cells [3] can also have immunoregulatory function and secrete IL-10 [4]. In order to obtain information on molecular mechanisms involved in anergy and immunoregulation, we have compared expression levels of 1176 genes in anergic, naive, and recently activated CD4 + T cells of the same specificity by gene array analysis. The results provide a plausible explanation for the anergic phenotype in terms of proliferation, provide new information on the surface phenotype of in vivo-generated anergic CD4 + T cells, and yield clues with regard to new candidate genes that may be responsible for the restricted cytokine production of in vivo-anergized CD4 + T cells. The molecular fingerprints of such T cells should enable the tracking of this small population in the normal organism and the study of their role in immunoregulation.

BACKGROUND: We have previously demonstrated that recombinant adeno-associated virus vectors expressing the influenza virus hemagglutinin (rAAV-HA) in skeletal muscle results in T-cell priming and muscle fiber destruction due to cross-presentation of HA by dendritic cells (DC). Based on controversial observations concerning the stability of non-self proteins expressed from rAAV vectors it is important to understand the factors influencing cross-presentation of transgene products following rAAV mediated gene transfer, in order to be able to use this vector safely in the clinic. METHODS: In order to understand the factors influencing in vivo cross-presentation of non-self proteins, we have retargeted the immunogenic lacZ protein in the context of rAAV from the cytoplasm to the cell surface and studied the activation of LacZ specific immune responses following intramuscular mediated gene transfer. In addition, using tools available for studying in vitro HA-specific T-cell activation, our aim was to identify the cell types involved in class I and class II restricted cross-presentation as well as the nature of the cross-presented material. RESULTS: By retargeting the lacZ protein in the context of rAAV to the cell membrane, we found that one of the factors influencing the efficiency of cross-presentation of non-self antigens is the localization of the transgene product within the target cells. Following rAAV-LacZ mediated gene transfer to the muscle we demonstrated that the membrane-bound form of LacZ resulted in target cell destruction, which is in stark contrast to the stability observed with rAAV-LacZ vectors expressing the cytoplasmic form of LacZ. Using an in vitro assay, we were able to show that dendritic cells (DC) in addition to B-cells cross-presented HA to class II restricted T-cells whereas only the former were able to activate class I restricted CD8+ T-cells. High-dose antigens were needed for efficient class I restricted T-cell priming, whereas class II restricted T-cells were activated by less antigen. CONCLUSION: The present results indicate that immune responses to non-self antigens expressed from rAAV vectors depend on the accessibility of such antigens to different local antigen-presenting cells.