Mathematical, statistical, and computational methods enable multi-disciplinary approaches that catalyse discovery. Together with experimental methods, they identify key hypotheses, define measurable observables and reconcile disparate results. This volume collects a representative sample of studies in T cell immunology that illustrate the benefits of modelling-experimental collaborations and which have proven valuable or even ground-breaking. Studies include thymic selection, T cell repertoire diversity, T cell homeostasis in health and disease, T cell-mediated immune responses, T cell memory, T cell signalling and analysis of flow cytometry data sets. Contributing authors are leading scientists in the area of experimental, computational, and mathematical immunology. Each chapter includes state-of-the-art and pedagogical content, making this book accessible to readers with limited experience in T cell immunology and/or mathematical and computational modelling.

This book reviews how mathematical and computational approaches can be useful to help us understand how killer T-cell responses work to fight viral infections. It also demonstrates, in a writing style that exemplifies the point, that such mathematical and computational approaches are most valuable when coupled with experimental work through interdisciplinary collaborations. Designed to be useful to immunoligists and viroligists without extensive computational background, the book covers a broad variety of topics, including both basic immunological questions and the application of these insights to the understanding and treatment of pathogenic human diseases.

"Taken together, the body of information contained in this book provides readers with a bird’s-eye view of different aspects of exciting work at the convergence of disciplines that will ultimately lead to a future where we understand how immunity is regulated, and how we can harness this knowledge toward practical ends that reduce human suffering. I commend the editors for putting this volume together." –Arup K. Chakraborty, Robert T. Haslam Professor of Chemical Engineering, and Professor of Physics, Chemistry, and Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA New experimental techniques in immunology have produced large and complex data sets that require quantitative modeling for analysis. This book provides a complete overview of computational immunology, from basic concepts to mathematical modeling at the single molecule, cellular, organism, and population levels. It showcases modern mechanistic models and their use in making predictions, designing experiments, and elucidating underlying biochemical processes. It begins with an introduction to data analysis, approximations, and assumptions used in model building. Core chapters address models and methods for studying immune responses, with fundamental concepts clearly defined. Readers from immunology, quantitative biology, and applied physics will benefit from the following: Fundamental principles of computational immunology and modern quantitative methods for studying immune response at the single molecule, cellular, organism, and population levels. An overview of basic concepts in modeling and data analysis. Coverage of topics where mechanistic modeling has contributed substantially to current understanding. Discussion of genetic diversity of the immune system, cell signaling in the immune system, immune response at the cell population scale, and ecology of host-pathogen interactions.

The immune system provides the host organism with defense mechanisms against invading pathogens and tumor development and it plays an active role in tissue and organ regeneration. Deviations from the normal physiological functioning of the immune system can lead to the development of diseases with various pathologies including autoimmune diseases and cancer. Modern research in immunology is characterized by an unprecedented level of detail that has progressed towards viewing the immune system as numerous components that function together as a whole network. Currently, we are facing significant difficulties in analyzing the data being generated from high-throughput technologies for understanding immune system dynamics and functions, a problem known as the ‘curse of dimensionality’. As the mainstream research in mathematical immunology is based on low-resolution models, a fundamental question is how complex the mathematical models should be? To respond to this challenging issue, we advocate a hypothesis-driven approach to formulate and apply available mathematical modelling technologies for understanding the complexity of the immune system. Moreover, pure empirical analyses of immune system behavior and the system’s response to external perturbations can only produce a static description of the individual components of the immune system and the interactions between them. Shifting our view of the immune system from a static schematic perception to a dynamic multi-level system is a daunting task. It requires the development of appropriate mathematical methodologies for the holistic and quantitative analysis of multi-level molecular and cellular networks. Their coordinated behavior is dynamically controlled via distributed feedback and feedforward mechanisms which altogether orchestrate immune system functions. The molecular regulatory loops inherent to the immune system that mediate cellular behaviors, e.g. exhaustion, suppression, activation and tuning, can be analyzed using mathematical categories such as multi-stability, switches, ultra-sensitivity, distributed system, graph dynamics, or hierarchical control. GB is supported by the Russian Science Foundation (grant 18-11-00171). AM is also supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness and FEDER grant no. SAF2016-75505-R, the “María de Maeztu” Programme for Units of Excellence in R&D (MDM-2014-0370) and the Russian Science Foundation (grant 18-11-00171).

The rapid development of new methods for immunological data collection – from multicolor flow cytometry, through single-cell imaging, to deep sequencing – presents us now, for the first time, with the ability to analyze and compare large amounts of immunological data in health, aging and disease. The exponential growth of these datasets, however, challenges the theoretical immunology community to develop methods for data organization and analysis. Furthermore, the need to test hypotheses regarding immune function, and generate predictions regarding the outcomes of medical interventions, necessitates the development of mathematical and computational models covering processes on multiple scales, from the genetic and molecular to the cellular and system scales. The last few decades have seen the development of methods for presentation and analysis of clonal repertoires (those of T and B lymphocytes) and phenotypic (surface-marker based) repertoires of all lymphocyte types, and for modeling the intricate network of molecular and cellular interactions within the immune systems. This e-Book, which has first appeared as a ‘Frontiers in Immunology’ research topic, provides a comprehensive, online, open access snapshot of the current state of the art on immune system modeling and analysis.

La 4e de couverture indique : "Any organism, to survive, must use a variety of defense mechanisms. A relatively recent evolutionary development is that of the adaptive immune system, carried to a quite sophisticated level by mammals. The complexity of this system calls for its encapsulation by mathematical models, and this book aims at the associated description and analysis. In the process, it introduces tools that should be in the armory of any current or aspiring applied mathematician, in the context of, arguably, the most effective system nature has devised to protect an organism from its manifold invisible enemies."

In this book, an interdisciplinary approach combining dynamic quantitative measurements with mathematical modelling is used to solve two different problems in molecular immunology. In the first part, structure and function of the gene-regulatory network that controls differentiation of type I T-helper (Th1) cells is investigated. By determining the network structure through an iterative process of modelling and experiments, the author shows that Th1 differentiation proceeds in two steps: In the early effector phase, the Th1 master transcription factor T-bet is controlled by an interferon-? dependent positive feedback loop, while in the later phase a second IL-12 dependent feedback maintains T-bet expression. The antigen signal acts as a switch between the two pathways. Moreover, it is shown that only T-bet expression in the late phase is predictive of the success of the differentiation process. Since T-bet expression in the late phase requires IL-12 stimulation, this work uncovers the molecular mechanisms behind the unique role of IL-12 in Th1 differentiation. In the second part, regulation of the transcription factor NFAT that mediates antigenic stimulation in T-cells is investigated. NFAT is activated by nuclear import upon dephosphorylation of multiple residues. Based on simultaneous measurements of NFAT subcellular localization and phosphorylation, a quantitative mathematical model of the NFAT regulatory network is developed and the underlying design principles are analyzed. In summary, the study exemplifies the necessity of a dynamic analysis at the systems level to understand complex biological processes.