Epigenetics of the Immune System

Dieter Kabelitz, Jaydeep Bhat

• Publisher: Academic Press
• Year: 2020
• Print ISBN: 9780128179642
• eBook ISBN: 9780128179659
• Topic: Medicine
• Subtopic: Immunology

Epigenetics of the Immune System focuses on different aspects of epigenetics and immunology, providing readers with the fundamental mechanisms relating to epigenetics and the immune system. This book provides in-depth information on immune cells as a toolbox in deciphering systematically regulated mechanisms using "omics" and computational biology approaches. In addition, the book presents the translational importance of epigenetics and the immune system in our understanding of pathophysiology in diseases and its therapeutic applications.- Provides an overview of most important immune mechanisms, the current status of epigenetics, and how both of them are brought together- Presents key principles of immune mechanisms in epigenetics, presenting current findings and key principles- Features in-depth chapter contributions from a wide range of international researchers and specialists in immunology, translational medicine and epigenetics- Merges two very large areas, covering the unique interrelatedness of epigenetics and immunology

Chapter 1

An introduction to immunology and epigenetics

Jaydeep Bhat; Dieter Kabelitz Institute of Immunology, University of Kiel, Kiel, Germany

Abstract

Immune cells are part of the most dynamic organ system in the body, which fights primarily against infections and maintains cellular integrity and homeostasis. Memory is a unique feature of the immune system, which enables immune cells to remember previous antigen exposure and to respond effectively upon rechallenge throughout lifetime. Immunological memory is the key feature which has helped to develop vaccines against a variety of diseases. However, the development, differentiation, and responsiveness of the many innate and adaptive immune cells are largely encoded in their genetic and epigenetic makeup. Though the genetic codes have been important in shaping person-specific immune responses, the (micro)environmental stimuli contribute most effectively to the shaping of molecular and cellular responses. Thus, a holistic understanding of the interface of epigenetics and the immune system is absolutely necessary. In this chapter, we introduce readers to the key concepts in immunology and epigenetics. Furthermore, we will conclude with a glimpse of the interdisciplinary future of epigenetics of the immune system.

Keywords

Immune cells; Immune response; Immune memory; Chromatin; RNA expression; Epigenomics

Contents

• Development of immune cells
• Dynamics of the immune response
• Immunological memory
• Basic overview of epigenetic regulation
• Genome architecture at primary structure scale: Cis-regulation through DNA elements
• Genome architecture at secondary structure scale: Trans-regulation through chromatin packaging and nucleosome positioning
• Genome architecture at tertiary structure scale: Long-range chromatic interactions and gene regulation within chromatin territory and compartments
• Posttranscriptional regulation of RNA expression
• Posttranslational modifications: Chromatin remodeling complexes and histones
• Posttranslational modifications: Nonhistone proteins
• Advancing technology and use of interdisciplinary approaches
• References

The immune system not only protects the organism against danger from the outside world (e.g., infections caused by bacteria, viruses, fungi, or parasites), but also maintains tolerance to self, and monitors cellular integrity by sensing stressed and malignant cells (“immune surveillance”). A key feature of the immune system is immunological memory, i.e., the capacity to rapidly respond with increased intensity upon secondary challenge with the same antigen (which forms the basis of vaccination). The immune system is composed of a multitude of cells and soluble factors that are important for the orchestration of immune responses and the bidirectional interaction between the immune system and other organ systems (e.g., the nervous system). Historically, the components of the immune system have been categorized as nonspecific (“innate”) and specific (“adaptive”) branches. The adaptive arm of immunity comprises B lymphocytes (B cells), which produce antibodies (immunoglobulins, Ig), and T lymphocytes (T cells), which are specific effector cells of cellular immunity. During development, both B cells and T cells undergo a rearrangement of germline-encoded genes coding for Ig and T-cell receptor (TCR), respectively, leading to an almost unlimited antibody and TCR repertoire in mature B-cell and T-cell compartments. Cells of the innate immune system including granulocytes, monocytes/macrophages, innate lymphoid cells (ILCs), natural killer (NK) cells do not express antigen-specific receptors (like B and T cells), but express a plethora of activating and inhibitory receptors that govern their functional activity. The communication between immune cells and their activation, migration, proliferative expansion, and differentiation is orchestrated by a broad range of cytokines including interleukins and chemokines. Some cells (like ILCs) are directly activated by interleukins, whereas others (like T cells) require antigenic stimulation to upregulate surface receptors, which then can mediate functional responses. For obvious reasons, “differentiation” is a continuous ongoing process, which governs the immune system from the early steps of embryonic development all the way to the regulation of immune responses in the mature immune system. All steps of immune cell development and differentiation are subject to epigenetic regulation.

Development of immune cells

All immune cells develop from a common hematopoietic stem cell (HSC), which gives rise to lineage-specific progenitor cells, i.e., common lymphoid progenitor (CLP) and common myeloid progenitor (CMP) cells. While these cells still maintain the potential for (unlimited) self-renewal, their capacity for differentiation is restricted to distinct cell lineages. CLP are the precursors of B cells, T cells, ILCs, and NK cells, whereas CMP give rise to granulocytes and monocytes/macrophages on one side and to immature dendritic cells (DCs) on the other side (Fig. 1). A detailed overview of immune cell development is available in standard text books [1].

Fig. 1 A cartoon of immune cell development. Immune cells develop from hematopoietic stem cells (HSC), which give rise to lineage-restricted progenitor cells, i.e., common lymphoid progenitors (CLP) and common myeloid progenitors (CMP) cells. CLP cells are progenitors of adaptive immune cells expressing clonally variable antigen receptors (B cells/BCR, T cells/TCR) and innate lymphocytes lacking antigen receptors (NK cells, innate lymphoid cells ILC). Common myeloid progenitors give rise to both granulocytes/monocytes/macrophages and immature dendritic cells (DC), which can mature into potent antigen-presenting cells. Once blood-borne monocytes migrate into tissue they differentiate into macrophages. Tissue-specific macrophages include Langerhans cells in the skin, Kupffer cells in the liver, and microglia in the brain.

T cells develop from precursor cells entering the thymus where they undergo sequential maturation steps characterized by lack of CD4 and CD8 expression (“double negative,” DN) but differential expression of CD44 and CD25. Rearrangement of the TCR β variable (V), diversity (D), and joining (J) gene segments occurs at the CD44^lowCD25^high DN3 stage, where also the branching of the second population of T cells expressing a γδ TCR instead of the conventional αβ TCR takes place [2]. Following the subsequent rearrangement of TCR Vα and Jα genes, randomly generated TCR αβ heterodimers are expressed on the cell surface, which then undergo positive and negative selection based on affinity of their TCRs for self-major histocompatibility complex (MHC) class I or class II molecules in the context of self-peptides available in the thymus. The autoimmune regulator (AIRE) plays a critical role in this process by controlling the expression of peripheral tissue antigens in medullary thymic epithelial cells [3]. Overall, thymic selection of T cells is associated with massive cell death. Thymocytes expressing TCRs with no or too low affinity for self-MHC die by neglect, whereas thymocytes expressing TCRs with high affinity for self-MHC (which might cause fatal autoimmunity if exported to the periphery) die by apoptosis. This process, termed central tolerance, ensures that the vast majority of T cells leaving the thymus express TCRs of intermediate affinity for self-MHC, which will allow them to recognize processed peptides in the context of MHC class II (CD4 T cells) or MHC class I (CD8 T cells) molecules. Central tolerance, however, does not work perfectly, and peripheral mechanisms are instrumental for the maintenance of self-tolerance. Among those, T regulatory cells (Treg) have a crucial function. Treg are characterized as CD4⁺ CD25^highCD127^low and express the specific transcription factor FoxP3. FoxP3-deficient mice develop lymphadenopathy and succumb to autoimmunity, and FOXP3 mutations in humans giving rise to immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome are similarly associated with autoimmune phenomena [4]. Demethylation of Treg-specific demethylated regions (TSDR) in the FOXP3 gene is required for the suppressive activity of Treg [5].

B-cell producing antibodies of the immunoglobulin isotypes IgM, IgG, IgD, IgE, a...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1: An introduction to immunology and epigenetics
• Chapter 2: Plant epigenetics and the ‘intelligent’ priming system to combat biotic stress
• Chapter 3: Understanding immune system development: An epigenetic perspective
• Chapter 4: Epigenetic mechanisms in the regulation of lymphocyte differentiation
• Chapter 5: Epigenetics mechanisms driving immune memory cell differentiation and function
• Chapter 6: Microbiota in the context of epigenetics of the immune system
• Chapter 7: Sequencing technologies for epigenetics: From basics to applications
• Chapter 8: Advances in single-cell epigenomics of the immune system
• Chapter 9: Machine learning and deep learning for the advancement of epigenomics
• Chapter 10: Systems immunology meets epigenetics
• Chapter 11: Epigenetic deregulation of immune cells in autoimmune and autoinflammatory diseases
• Chapter 12: Epigenetics of allergies: From birth to childhood
• Chapter 13: Epigenetic regulation of normal hematopoiesis and its dysregulation in hematopoietic malignancies
• Chapter 14: Impact of epigenetic modifiers on the immune system
• Index