The case for absolute ligand discrimination : modeling information processing and decision by immune T cells

Some cells have to take decision based on the quality of surroundings ligands, almost irrespective of their quantity, a problem we name "absolute discrimination". An example of absolute discrimination is recognition of not-self by immune T Cells. We show how the problem of absolute discrimination can be solved by a process called "adaptive sorting". We review several implementations of adaptive sorting, as well as its generic properties such as antagonism. We show how kinetic proofreading with negative feedback implements an approximate version of adaptive sorting in the immune context. Finally, we revisit the decision problem at the cell population level, showing how phenotypic variability and feedbacks between population and single cells are crucial for proper decision

The unbearable lightness of bone marrow homeostasis

The anatomical and functional dimensions of bone marrow topography have been at the forefront of modern bone and immunological research for many years and remain a source of complexity and perplexity due to the multitude of microhabitats within this microenvironment. In fact, research has uncovered fascinating functional aspects of bone marrow residents, and the bone marrow niche has been identified as the foremost reservoir of a variety of cells including hematopoietic, skeletal and endothelial stem/progenitor cells. The physical interactions of the marrow residents, combined with the release of cytokines and growth factors, organize well-defined operative compartments, which preserve bone and immune cell homeostasis. In a simplistic view, both the hematopoietic and bone marrow stromal (mesenchymal) stem/progenitor cell populations dwell at the interface between the endosteum and the bone marrow area (endosteal niche) and in the perivascular space (vascular niche). Indeed, the tantalizing hypothesis of bone marrow regulatory dependency on these niches is supported by current research insofar as the increase in the number of osteoblasts results in a concomitant increase in the hematopoietic population, indicating that the osteoblasts and the endosteal niche are key components of HSC maintenance. On the other hand, impaired function of the vascular niche compromises the endosteal niche's ability to support hematopoiesis. These fascinating discoveries indicate that there are strong ties between bone marrow inhabitants within the confines of the bone marrow itself. When these ties fail, niche-niche communication suffers and results in reduced bone formation, enfeebled hematopoiesis and unrestrained HSC migration through blood circulation. This study focused on the extraordinary homeostatic equilibrium and function of both bone and immune cells within the spatially defined microenvironment of bone marrow. But how important is the anatomically outlined scenery in which the bone marrow entity supports and hosts the hematopoietic elements

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Il-15/il-15rα signalling and synaptic transmission: a crosstalk between the immune and the nervous system?

Immune and nervous system have been traditionally considered separately, but from ‘90s many studies had unraveled the deep interconnection and interdependence between these two systems, enough to coin the term “neuroimmune system” to define this relationship. While it was well known that central nervous system (CNS) actively communicates with the immune system to control immune responses both centrally and peripherally, the opposite action was just recently discovered. Related to the role of immune system in defending and react, the interactions between immune system and CNS have been classically studied in contexts of neuroinflammation such as trauma, injury and disease [1] [2]. Recent evidences about the neuroinflammatory process in non-pathological conditions and the discovery of the important involvement of adaptive immune system in healthy brain development and activity [3], have opened many questions about physiological neuroimmune cross-talk. In this view, the cytokine network, well known to operate in a bidirectional way affecting both immune and nervous system, has a pivotal role in neuroimmune cross-talk [4]. Traditionally seen as immunomodulators, in the last years has been evident that cytokines are also potent neuromodulators [5]. In the complex cytokine system, interleukin 15 (IL-15) is considered a bridge between adaptive and innate immune system and it is one of the first upregulated cytokines in neuroinflammation [6]. It has many bioregulatory roles which range from those of modulator of selected adaptive immune responses [7] [8] and central player in the development and homeostasis of several immunocyte populations [9] to those of a potent, general inhibitor of apoptosis in multiple systems [9]. Interestingly, has been shown that IL-15 and IL-15Rα deletions affect memory and neurotransmitters concentration suggesting a major role of this signalling in cerebral functions which cannot be compensated during the development [10] [11] [12]. IL-15Rα KO mice, in particular, show decreased retention of spatial memory and contextual fear, both related to hippocampus-dependent memory, and alteration in GABA concentration. Their hippocampal ultrastructure is, however, well preserved, suggesting that the modulatory changes may involve neural plasticity even if the exact role of IL15 in modulating neurotransmission has not been investigated so far. The understandings about the mechanism by which IL-15/IL-15Rα system affect the synaptic transmission may be useful to get insight into the mechanisms of cross talk between the immune and the nervous system and eventually to develop strategies to treat pathologies whose symptoms are memory impairments and neuroinflammation

Parasite excretory-secretory products and their effects on metabolic syndrome

Obesity, one of the main causes of metabolic syndrome (MetS), is an increasingly common health and economic problem worldwide, and one of the major risk factors for developing type 2 diabetes and cardiovascular disease. Chronic, low-grade inflammation is associated with MetS and obesity. A dominant type 2/anti-inflammatory response is required for metabolic homeostasis within adipose tissue: during obesity, this response is replaced by infiltrating, inflammatory macrophages and T cells. Helminths and certain protozoan parasites are able to manipulate the host immune response towards a TH2 immune phenotype that is beneficial for their survival and there is emerging data that there is an inverse correlation between the incidence of MetS and helminth infections, suggesting that, as with autoimmune and allergic diseases, helminths may play a protective role against MetS disease. Within this review, we will focus primarily on the excretory-secretory products that the parasites produce to modulate the immune system and discuss their potential use as therapeutics against MetS and its associated pathologies

libtissue - implementing innate immunity

In a previous paper the authors argued the case for incorporating ideas from innate immunity into articficial immune systems (AISs) and presented an outline for a conceptual framework for such systems. A number of key general properties observed in the biological innate and adaptive immune systems were hughlighted, and how such properties might be instantiated in artificial systems was discussed in detail. The next logical step is to take these ideas and build a software system with which AISs with these properties can be implemented and experimentally evaluated. This paper reports on the results of that step - the libtissue system.Comment: 8 pages, 4 tables, 5 figures, Workshop on Artificial Immune Systems and Immune System Modelling (AISB06), Bristol, U

Controversies concerning thymus-derived regulatory T cells: fundamental issues and a new perspective

Thymus-derived regulatory T cells (Tregs) are considered to be a distinct T-cell lineage that is genetically programmed and specialised for immunosuppression. This perspective is based on the key evidence that CD25(+) Tregs emigrate to neonatal spleen a few days later than other T cells and that thymectomy of 3-day-old mice depletes Tregs only, causing autoimmune diseases. Although widely believed, the evidence has never been reproduced as originally reported, and some studies indicate that Tregs exist in neonates. Thus we examine the consequences of the controversial evidence, revisit the fundamental issues of Tregs and thereby reveal the overlooked relationship of T-cell activation and Foxp3-mediated control of the T-cell system. Here we provide a new model of Tregs and Foxp3, a feedback control perspective, which views Tregs as a component of the system that controls T-cell activation, rather than as a distinct genetically programmed lineage. This perspective provides new insights into the roles of self-reactivity, T cell–antigen-presenting cell interaction and T-cell activation in Foxp3-mediated immune regulation