Resilience after a nuclear accident: readiness in using mobile phone applications to measure radiation and health indicators in various groups (SHAMISEN SINGS project).

An anonymous web-based survey was developed to check different aspects (SHAMISEN SINGS project): stakeholder awareness and perceptions of available mobile applications (apps) for measuring ionising radiation doses and health/well-being indicators; whether they would be ready to use them in the post-accidental recovery; and what are their preferred methodologies to acquire information etc. The results show that participation of the citizens would be most beneficial during post-accident recovery, providing individual measurements of external ionizing dose and health/well-being parameters, with possible follow-up. Also, participants indicated different preferences for sources to gain knowledge on ionising radiation and for the functions that an ideal app should have. The level of awareness and readiness to use apps to measure ionising radiation dose depended on two main aspects: individual differences (age & gender) and whether people were from countries affected by the previous major accidents. We concluded that stakeholders could have benefits from the data management plan: (1) it potentiates resilience at individual and community level; (2) citizens' measurements contribute to environmental monitoring and public health screening; (3) linkages between different types of data (environmental exposure, individual behavioural diaries, and measurements of health indicators) allow to perform more rigorous epidemiological studies.

Monocytic myeloid-derived suppressor cells home to tumor-draining lymph nodes via CCR2 and locally modulate the immune response.

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.

The SHAMISEN Recommendations on preparedness and health surveillance of populations affected by a radiation accident.

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.

Stakeholder participation in nuclear and radiological emergency preparedness and recovery in Spain: benefits and challenges of working together.

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.

Pattern Recognition by CD6: A Scavenger-Like Lymphocyte Receptor.

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.

Mesenchymal stem cells: myths and reality.

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.

CD5 as a Target for Immune-Based Therapies.

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.

[The intestinal microbiota: a boost for antitumor treatments]. / Nos bactéries commensales - un coup de pouce pour les thérapies antitumorales.

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.

Adenosine triphosphate acts as a paracrine signaling molecule to reduce the motility of T cells.

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.

Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues.

Macrophages are extremely versatile cells that adopt a distinct phenotype in response to a changing microenvironment. Consequently, macrophages are involved in diverse functions, ranging from organogenesis and tissue homeostasis to recognition and destruction of invading pathogens. In cancer, tumor-associated macrophages (TAM) often contribute to tumor progression by increasing cancer cell migration and invasiveness, stimulating angiogenesis, and suppressing anti-tumor immunity. Accumulating evidence suggests that these different functions could be exerted by specialized TAM subpopulations. Here, we discuss the potential underlying mechanisms regulating TAM specialization and elaborate on TAM heterogeneity in terms of their ontogeny, activation state, and intra-tumoral localization. In addition, parallels are drawn between TAM and macrophages in other tissues. Together, a better understanding of TAM diversity could provide a rationale for novel strategies aimed at targeting the most potent tumor-supporting macrophages.

Instruction of myeloid cells by the tumor microenvironment: Open questions on the dynamics and plasticity of different tumor-associated myeloid cell populations.

The versatility and plasticity of myeloid cell polarization/differentiation has turned out to be crucial in health and disease, and has become the subject of intense investigation during the last years. On one hand, myeloid cells provide a critical contribution to tissue homeostasis and repair. On the other hand, myeloid cells not only play an important role as first line defense against pathogens but also they are involved in a broad array of inflammation-related diseases such as cancer. Recent studies show that macrophages can exist in different activation states within the same tumor, underlining their plasticity and heterogeneity. In this review, we will discuss recent evidence on how the tumor microenvironment, as it evolves, shapes the recruitment, function, polarization and differentiation of the myeloid cell compartment, leading to the selection of myeloid cells with immunosuppressive and angiogenic functions that facilitate tumor progression and dissemination.

The pros and cons of chemokines in tumor immunology.

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.

Agrin is required for survival and function of monocytic cells.

Agrin, an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), is expressed by cells of the hematopoietic system but its role in leukocyte biology is not yet clear. Here we demonstrate that agrin has a crucial, nonredundant role in myeloid cell development and functions. We have identified lineage-specific alterations that affect maturation, survival and properties of agrin-deficient monocytic cells, and occur at stages later than stem cell precursors. Our data indicate that the cell-autonomous signals delivered by agrin are sensed by macrophages through the α-DC (DG) receptor and lead to the activation of signaling pathways resulting in rearrangements of the actin cytoskeleton during the phagocytic synapse formation and phosphorylation of extracellular signal-regulated kinases (Erk 1/2). Altogether, these data identify agrin as a novel player of innate immunity.

The critical role of agrin in the hematopoietic stem cell niche.

Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called "hematopoietic niches," through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin(-)Sca1(+)c-Kit(+) (LSK) cells express the α-dystroglycan receptor for agrin. In vitro, agrin-deficient MSCs were less efficient in supporting proliferation of mouse Lin(-)c-Kit(+) cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn(-/-)). Agrin-deficient mice displayed in vivo apoptosis of CD34(+)CD135(-) LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells.

The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6.

BACKGROUND AND AIMS: Inflammatory CC chemokines have long been associated with cancer, but unequivocal evidence of a role in clinically relevant models of carcinogenesis is lacking. D6, a promiscuous decoy receptor that scavenges inflammatory CC chemokines, plays a non-redundant role in reducing the inflammatory response in various organs. As inflammation is a key player in the development of inflammatory bowel disease (IBD) and IBD-associated colorectal cancer, we investigated D6 expression in human colitis and colon cancer, and its role in experimental colitis and inflammation-associated colon cancer. RESULTS: In humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as the mucosa of control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than wild-type mice and failed to resolve colitis, with significantly higher levels of several pro-inflammatory chemokines. In bone marrow chimeric mice, the ability of D6 to regulate colitis was tracked to the stromal/lymphatic compartment, with no contribution of haemopoietic cells. Finally, after administration of the carcinogen azoxymethane, D6(-/-) mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with wild-type mice. CONCLUSIONS: D6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and the development of inflammation-associated colon cancer. Our results reveal a new unexpected role for the lymphatic system in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumour promotion and progression.

A specific signalling signature characterizes the development of naturally occurring and antigen-specific regulatory T cells.

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.

Towards identification of the mechanisms of action of parasite-derived peptide GK1 on the immunogenicity of an influenza vaccine.

Previous studies have shown that the synthetic peptide GK1, derived from Taenia crassiceps cysticerci, enhances the immunogenicity of the commercial inactivated influenza vaccine Fluzone in both young and aged mice. In particular, antibody responses were much improved. Since GK1 is a peptide and is rapidly cleared from the body, it offers the possibility to improve vaccine performance without undesirable effects. This study was therefore designed to understand the mechanisms of action involved in the adjuvant properties of GK1. For this, transgenic mice expressing a T-cell receptor specific for an epitope from the influenza virus hemagglutinin (HA) protein were employed. The GK1 peptide significantly increased the in vivo proliferative response of HA-specific CD4+ T cells when it was coimmunized with the HA epitope. Dendritic cells treated in vitro with GK1 were capable of enhancing T-cell activation. Furthermore, in synergy with lipopolysaccharide, GK1 enhanced the expression of major histocompatibility complex class II and costimulatory molecules of dendritic cells and promoted the secretion of proinflammatory cytokines and chemokines upon antigen-driven T-cell interaction. These data provide important insights into the mechanism that underlies the GK1 adjuvant capacity observed previously and underline the feasibility of using the transgenic mouse model described herein as a tool for investigation of the modes of action of different influenza vaccine adjuvants.

Tolerance induction to self antigens by peripheral dendritic cells.

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.

Origin of regulatory T cells with known specificity for antigen.

T cell receptor agonists can induce the differentiation of regulatory T (T(R)) cells. We report here that the immunoglobulin kappa-controlled expression of an agonist in different cell types correlated with the phenotype of the generated T(R) cells. We found that aberrant expression on thymic stroma yielded predominantly CD4(+)CD25(+) T(R) cells, which--under physiological conditions--may be induced by ectopically expressed organ-specific antigens and thus prevent organ-specific autoimmunity. Expression of the agonist antigen by nonactivated hematopoietic cells produced mostly CD4(+)CD25(-) T(R) cells. This subset can be derived from mature monospecific T cells without "tutoring" by other T cells and can be generated in the absence of a functioning thymus. Suppression of CD4(+) T cell proliferative responses by both CD25(+) and CD25(-) subsets was interleukin 10 (IL-10) independent and was overcome by IL-2. These data suggest that distinct pathways can be exploited to interfere with unwanted immune responses.