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This book describes a computational model of the immune system reaction, C-ImmSim. The book presents the basic model as well as the various customizations to implement the description of different diseases and the way they have been used to produce new knowledge either from hypothesis or from experimental data. The book can be used as a practical guide to implement a computational model with which to study a specific disease and to try to address realistic clinical questions.

The community of cells lining our airways plays a collaborative role in the preservation of immune homeostasis in the lung and provides protection from the pathogens and pollutants in the air we breathe. In addition to its structural attributes that provide effective mucociliary clearance of the lower airspace, the airway epithelium is an immunologically active barrier surface that senses changes in the airway environment and interacts with resident and recruited immune cells. Single-cell RNA-sequencing is illuminating the cellular heterogeneity that exists in the airway wall and has identified novel cell populations with unique molecular signatures, trajectories of differentiation and diverse functions in health and disease. In this Review, we discuss how our view of the airway epithelial landscape has evolved with the advent of transcriptomic approaches to cellular phenotyping, with a focus on epithelial interactions with the local neuronal and immune systems.In this Review, Lloyd and Hewitt describe our contemporary understanding of the airway epithelial cell landscape. They highlight the new epithelial cell types that have been recently discovered and explain how epithelial cells interact with the immune and nervous systems to shape immunity in the airways.

Key Points Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is present in two complexes: mTORC1 and mTORC2. mTORC1 is the main energy and nutrient sensor of the cell: it senses the presence of amino acids, glucose, lipids and ATP to enable efficient activation of the network in response to growth factors, Toll-like receptor (TLR) ligands and cytokines. Activation of the mTOR pathway usually promotes an anabolic response that induces the synthesis of nucleic acids, proteins and lipids. In addition, it stimulates glycolysis and mitochondrial respiration. Emerging data suggest that this metabolic reconfiguration is required for specific effector functions in myeloid cells. Translational control of gene expression in myeloid immune cells has emerged as one way in which mTORC1 controls cellular processes such as migration, expression of type I interferon and pro-inflammatory or anti-inflammatory cytokines, and metabolic reprogramming. Counterintuitively, inhibition of mTORC1 during TLR triggering generally promotes interleukin-12 (IL-12) production and inhibits expression of IL-10 and type I interferon by dendritic cells (DCs); it also augments their T cell-stimulatory capacity. Inhibition of mTORC2 enhances a pro-inflammatory response and IL-12 production in DCs. Inhibition of mTORC1 in macrophages promotes autophagy, which is important for intracellular pathogen killing and clearance of ingested complex lipids such as low-density lipoprotein (LDL) cholesterol. mTORC2 is especially important for cell polarity and chemotaxis in neutrophils and mast cells. mTORC2 controls the leading edge as well as tail retraction during chemotactic migration. Activation of mTORC1 in NK cells by IL-15 triggers a glycolytic response, which is important for their proliferation and acquisition of cytotoxicity. The rapid response of innate immune cells requires metabolic reprogramming to support their specific effector functions. As discussed here, mTOR is a key regulator of this process: it senses the environmental and intracellular nutritional status of innate immune cells to dictate and optimize the inflammatory response. The innate immune system is central for the maintenance of tissue homeostasis and quickly responds to local or systemic perturbations by pathogenic or sterile insults. This rapid response must be metabolically supported to allow cell migration and proliferation and to enable efficient production of cytokines and lipid mediators. This Review focuses on the role of mammalian target of rapamycin (mTOR) in controlling and shaping the effector responses of innate immune cells. mTOR reconfigures cellular metabolism and regulates translation, cytokine responses, antigen presentation, macrophage polarization and cell migration. The mTOR network emerges as an integrative rheostat that couples cellular activation to the environmental and intracellular nutritional status to dictate and optimize the inflammatory response. A detailed understanding of how mTOR metabolically coordinates effector responses by myeloid cells will provide important insights into immunity in health and disease.

As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4 + and CD8 + T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC-based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential.

Key Points Most of our understanding of memory T cell generation, function and maintenance comes from mouse studies, which cannot recapitulate the exposure to diverse antigens and microbiota that occurs over many decades in humans. Memory T cell frequency dynamically changes throughout the human lifetime and this can be divided into three phases: memory generation, memory homeostasis and immunosenescence. CD45RO + CD45RA − T cells comprise diverse memory T cell subsets, including central memory T (T CM ) cells, effector memory T (T EM ) cells, stem cell memory T (T SCM ) cells and tissue-resident memory T (T RM ) cells, which are heterogeneous in their generation, distribution and function. Memory T cells that are specific for antigens from ubiquitous pathogens and possibly from endogenous flora are generated early in life and are preferentially compartmentalized at the sites of infection throughout adulthood. Human memory T cells in diverse tissue sites are homeostatically maintained, potentially through tonic T cell receptor signalling, and can show extensive cross reactivity and can persist for decades. The induction of memory CD4 + and CD8 + T cells through vaccination can enhance protection against pathogens, and might be improved by considering the anatomical location and the timing of vaccine administration during the early stages of life. Most of our understanding of immunological memory comes from studies in mice. However, these studies cannot recapitulate the exposure to numerous diverse pathogens that occurs over decades in humans. But, as reviewed here, recent studies focusing on human memory T cells are revealing important features of these cells, including subset heterogeneity and spatial compartmentalization. Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.

CD8 T cells comprising the memory pool display considerable heterogeneity, with individual cells differing in phenotype and function. This review will focus on our current understanding of heterogeneity within the antigen-specific memory CD8 T cell compartment and classifications of memory CD8 T cell subsets with defined and discrete functionalities. Recent data suggest that phenotype and/or function of numerically stable circulatory memory CD8 T cells are defined by the age of memory CD8 T cell (or time after initial antigen-encounter). In addition, history of antigen stimulations has a profound effect on memory CD8 T cell populations, suggesting that repeated infections (or vaccination) have the capacity to further shape the memory CD8 T cell pool. Finally, genetic background of hosts and history of exposure to diverse microorganisms likely contribute to the observed heterogeneity in the memory CD8 T cell compartment. Extending our tool box and exploring alternative mouse models (i.e., \"dirty\" and/or outbred mice) to encompass and better model diversity observed in humans will remain an important goal for the near future that will likely shed new light into the mechanisms that govern biology of memory CD8 T cells.

BACKGROUNDUnderstanding what determines the between-host variability in infection dynamics is a key issue to better control the infection spread. In particular, pathogen clearance is desirable over rebounds for the health of the infected individual and its contact group. In this context, the Porcine Respiratory and Reproductive Syndrome virus (PRRSv) is of particular interest. Numerous studies have shown that pigs similarly infected with this highly ubiquitous virus elicit diverse response profiles. Whilst some manage to clear the virus within a few weeks, others experience prolonged infection with a rebound. Despite much speculation, the underlying mechanisms responsible for this undesirable rebound phenomenon remain unclear.RESULTSWe aimed at identifying immune mechanisms that can reproduce and explain the rebound patterns observed in PRRSv infection using a mathematical modelling approach of the within-host dynamics. As diverse mechanisms were found to influence PRRSv infection, we established a model that details the major mechanisms and their regulations at the between-cell scale. We developed an ABC-like optimisation method to fit our model to an extensive set of experimental data, consisting of non-rebounder and rebounder viremia profiles. We compared, between both profiles, the estimated parameter values, the resulting immune dynamics and the efficacies of the underlying immune mechanisms. Exploring the influence of these mechanisms, we showed that rebound was promoted by high apoptosis, high cell infection and low cytolysis by Cytotoxic T Lymphocytes, while increasing neutralisation was very efficient to prevent rebounds.CONCLUSIONSOur paper provides an original model of the immune response and an appropriate systematic fitting method, whose interest extends beyond PRRS infection. It gives the first mechanistic explanation for emergence of rebounds during PRRSv infection. Moreover, results suggest that vaccines or genetic selection promoting strong neutralising and cytolytic responses, ideally associated with low apoptotic activity and cell permissiveness, would prevent rebound.

Key Points Candida albicans is the most important fungal pathogen in humans, and it causes both mucosal and systemic fungal infections. Innate immune recognition by pattern recognition receptors (PRRs) is the first step for activation of host defence mechanisms during Candida infections. C-type lectin receptors (CLRs) are the main family of PRRs involved in recognition of Candida species, but Toll-like receptors, NOD-like receptors and RIG-I-like receptors are also involved in the antifungal response. Neutrophils, monocytes and macrophages are the main immune cell populations responsible for host defence against systemic candidiasis, whereas T helper 1 (T H 1) cells, T H 17 cells and innate lymphoid cells are mainly responsible for protection against Candida infections at mucosal surfaces. C. albicans and components from its cell wall, particularly β-glucans, have the capacity to induce epigenetic reprogramming of innate immune cells, generating a de facto innate immune memory that has been termed 'trained immunity'. Systems biology approaches combining innovative genomic, microbiome and functional data open new possibilities for identifying key mechanisms in the pathophysiology of fungal infections. Future efforts need to combine cutting-edge molecular and cell-biological techniques with translational approaches in order to gain a better understanding of the host immune response to Candida infections and enable the design of novel antifungal strategies. This Review describes the host immune response to Candida fungal infections. The authors detail the innate and adaptive immune mechanisms, as well as the non-immune mechanisms, that are involved in the antifungal response. They also discuss emerging evidence suggesting that both innate and adaptive immune cells contribute to immune memory against Candida species. The immune response to Candida species is shaped by the commensal character of the fungus. There is a crucial role for discerning between colonization and invasion at mucosal surfaces, with the antifungal host defence mechanisms used during mucosal or systemic infection with Candida species differing substantially. Here, we describe how innate sensing of fungi by pattern recognition receptors and the interplay of immune cells (both myeloid and lymphoid) with non-immune cells, including platelets and epithelial cells, shapes host immunity to Candida species. Furthermore, we discuss emerging data suggesting that both the innate and adaptive immune systems display memory characteristics after encountering Candida species.

Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.

Immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is central to long-term control of the current pandemic. Despite our rapidly advancing knowledge of immune memory to SARS-CoV-2, understanding how these responses translate into protection against reinfection at both the individual and population levels remains a major challenge. An ideal outcome following infection or after vaccination would be a highly protective and durable immunity that allows for the establishment of high levels of population immunity. However, current studies suggest a decay of neutralizing antibody responses in convalescent patients, and documented cases of SARS-CoV-2 reinfection are increasing. Understanding the dynamics of memory responses to SARS-CoV-2 and the mechanisms of immune control are crucial for the rational design and deployment of vaccines and for understanding the possible future trajectories of the pandemic. Here, we summarize our current understanding of immune responses to and immune control of SARS-CoV-2 and the implications for prevention of reinfection.The duration of immunity to coronavirus disease 2019 (COVID-19) from prior infection and longer-term risk of reinfection are currently unclear. Cromer and colleagues discuss the immune control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the implications of this for the future control of the pandemic.