Key features:
* Contributions from leading authorities * Informs and updates on all the latest developments in the field
Advances in Immunology, a long-established and highly respected publication, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for the future. Contributions from leading authorities Informs and updates on all the latest developments in the field
Front Cover 1
Advances in Immunology 4
Copyright 5
Contents 6
Contributors 8
Chapter One: Regulation of CD4 and CD8 Coreceptor Expression and CD4 Versus CD8 Lineage Decisions 10
1. Introduction 11
2. CD4 and CD8 Coreceptors and Thymocyte Selection 13
2.1. Molecular timers defining the duration of positive selection signals 13
2.2. Quencher of free Lck to assure MHC restriction of TCR 16
3. Cis-Regulatory Elements for Genes Encoding CD4 and CD8 Coreceptors 19
3.1. Regulatory elements for Cd4 19
3.2. Regulatory elements or Cd8a/Cd8b1 24
4. Transcription Factors Regulating CD4 and CD8 Expression and Lineage Choice in the Thymus 28
4.1. Runx proteins and Thpok 28
4.2. AP4 30
4.3. Mazr 33
4.4. Other factors 34
5. Regulation of CD4 and CD8 in Mature T Cells 36
5.1. Epigenetic regulation of Cd4 36
5.2. Plasticity of CD4+ intraepithelial T cells 38
6. Cytokine Receptor Signals and CD4/CD8 Lineage Commitment 39
6.1. The role of IL-7R signals in the kinetic signaling model 39
6.2. Analysis of mice lacking IL-7Ra or IL-2R. 40
7. Concluding Remarks 41
Acknowledgments 42
References 42
Chapter Two: Mast Cells Integrated Actions with Eosinophils and Fibroblasts in Allergic Inflammation: Implications for Th... 50
1. Introduction 51
2. Mast Cells and Eosinophils in Allergic Inflammation 54
3. Mast Cell Eosinophil Cross-Talk: The Allergic Effector Unit 57
3.1. Soluble interactions 59
3.2. Physical interactions 61
4. Fibroblasts from Repair to Fibrosis in Allergic Inflammation 66
5. Mast Cells and Fibroblasts: Bidirectional Interactions 68
6. Eosinophls and Fibroblasts: Bidirectional Interactions 71
7. Therapeutic Implications of Mast Cells, Eosinophils, and Fibroblasts Cross Talks for Allergic Inflammation 72
8. Future Drugs 77
9. Conclusions 78
Acknowledgments 79
References 79
Chapter Three: Positive-Selection-Inducing Self-Peptides Displayed by Cortical Thymic Epithelial Cells 96
1. Introduction 97
2. Characterization of Positive-Selection-Inducing Peptides 99
2.1. TCR affinity of selecting peptide-MHC complexes 99
2.2. Identification of selecting peptides by mass spectrometry 101
2.3. Selecting peptides affect T cell responsiveness 103
2.4. Single-peptide experiments 104
3. Antigen Processing in Cortical Thymic Epithelial Cells 106
3.1. Cortical thymic epithelial cells 106
3.2. Thymoproteasome 108
3.3. Cathepsin L and thymus-specific serine protease 110
3.4. Autophagy 111
4. Concluding Remarks 112
Acknowledgment 113
References 113
Chapter Four: Group 2 Innate Lymphoid Cells in the Regulation of Immune Responses 120
1. Introduction 121
2. Meet the Family 122
3. Drawing Parallels Between ILC Cells and T Cells 123
4. Human and Murine ILC2 Cell Phenotypes 124
5. ILC2 Cell Development 125
6. The Cytokine Factory 129
6.1. IL-13 129
6.2. IL-5 130
6.3. IL-4 131
6.4. IL-9 132
6.5. Amphiregulin and IL-6 133
7. Sensing of the Environment by ILC2 Cells 133
7.1. IL-25 and IL-33 receptors 134
7.2. TL1A/DR3 137
7.3. Common gamma-chain receptors 137
7.4. IL-7/IL-7Ra 138
7.5. IL-2/IL-2Ra 139
7.6. IL-9/IL-9R 140
7.7. TSLP–TSLPR 140
7.8. IL-4/IL-4Ra 140
7.9. Lipid signaling 141
7.9.1. CysLT1R 141
7.9.2. CRTH2 141
7.9.3. VPAC2 142
7.9.4. FPR2 142
7.10. Other known signaling pathways 142
7.10.1. STAT6 signaling 142
7.10.2. KLRG1 143
7.10.3. CMKLR1 143
7.10.4. ICOS and GITR 143
8. The Black Sheep of the Family: The Dermal ILC2 Cell 144
9. Are ILC2 Cells Upstream or Downstream of T Cells? 147
10. Concluding Remarks 149
References 150
Chapter Five: Microbes and B Cell Development 164
1. Microbiota 165
1.1. Overview of microbiota and microbiome 165
1.2. Commensal/mutualistic microbes in health and disease 166
1.3. The immune system in host–microbe homeostasis 166
2. Early-Life B Cell Development and the Gut 167
2.1. Links between the gut and primary immunoglobulin diversification 167
2.2. Ig diversification and selection in rabbits 168
2.3. Ig diversification and selection in the bursa of Fabricius 170
2.4. Lessons from sheep and pigs 172
2.5. Perspectives on the role of the gut in B cell biology early in life 174
2.6. B cell development in the mouse lamina propria early in life 174
3. Microbial Influence on Immunoglobulin Production 176
3.1. Microbial influence on IgA production 176
3.2. Microbial influence on IgE Production 177
4. B Lineage Cell Influence on Commensal Microbe Ecology 178
5. Concluding Remarks 181
Acknowledgments 181
References 181
Index 188
Contents of Recent Volumes 194
Color Plate 209
Regulation of CD4 and CD8 Coreceptor Expression and CD4 Versus CD8 Lineage Decisions
Takeshi Egawa1 Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
1 Corresponding author: email address: tegawa@wustl.edu
Abstract
During blood cell development, hematopoietic stem cells generate diverse mature populations via several rounds of binary fate decisions. At each bifurcation, precursors adopt one fate and inactivate the alternative fate either stochastically or in response to extrinsic stimuli and stably maintain the selected fates. Studying of these processes would contribute to better understanding of etiology of immunodeficiency and leukemia, which are caused by abnormal gene regulation during the development of hematopoietic cells. The CD4+ helper versus CD8+ cytotoxic T-cell fate decision serves as an excellent model to study binary fate decision processes. These two cell types are derived from common precursors in the thymus. Positive selection of their TCRs by self-peptide presented on either MHC class I or class II triggers their fate decisions along with mutually exclusive retention and silencing of two coreceptors, CD4 and CD8. In the past few decades, extensive effort has been made to understand the T-cell fate decision processes by studying regulation of genes encoding the coreceptors and selection processes. These studies have identified several key transcription factors and gene regulatory networks. In this chapter, I will discuss recent advances in our understanding of the binary cell fate decision processes of T cells.
Keywords
Thymocyte selection
Lineage commitment
Plasticity
Transcription
1 Introduction
Why is it important to study the regulation of CD4 and CD8 expression?
T lymphocytes are the major players in adaptive immunity. In immune responses against viral infection, innate immune cells rapidly react to pathogen invasion through recognition of pathogen-associated molecular patterns. Yet in many situations, pathogen eradication and the establishment of immunological memory require a greater magnitude of sustainable immune responses by adaptive immune cells. T cells are critical components of adaptive immune responses by functioning as effector cells to eliminate pathogen. T cells also provide adequate “help” to other cell types via expression of cytokines and adhesion molecules. The former function is mediated mainly by CD8+ cytotoxic T cells and the latter is mediated by CD4+ helper T cells.
T-cell development from multipotent progenitors (MPPs) or common lymphoid progenitors (CLPs) is initiated in the thymus (Rothenberg, 2014). Expression of CD4 and CD8 coreceptors defines four major populations of thymocytes at distinct developmental stages (Ellmeier, Sawada, & Littman, 1999). The most immature T-cell progenitors express neither CD4 nor CD8, thus called double negative (DN) thymocytes. DN thymocytes are further divided based on the expression of CD25 and CD44 into four subsets called DN1 through DN4 (Godfrey, Kennedy, Suda, & Zlotnik, 1993; Pearse et al., 1989; Rothenberg, 2014). MPPs or CLPs commit to the T-cell lineage in response to the signal through Notch1 and expression of the transcription factors Bcl11b and Tcf7 (also known as TCF1) at the CD44+CD25+ DN2 stage, and subsequently undergo selection for successful Tcrb rearrangements at the CD44−CD25+ DN3 stage (beta selection) (Ikawa et al., 2010; Li, Burke, et al., 2010; Li, Leid, & Rothenberg, 2010). After beta selection, thymocytes initiate proliferation as they transit to the CD44−CD25− DN4 stage and subsequently turn on expression of CD4 and CD8 (Ellmeier et al., 1999; Fehling, Krotkova, Saint-Ruf, & von Boehmer, 1995; Hoffman et al., 1996). In the C57BL6 genetic background, surface CD8 expression increases prior to CD4 (CD8 immature single positive, ISP) and the developing thymocytes subsequently become CD4+CD8+ double positive (DP) cells. DP thymocytes are finally selected for the expression of αβTCR with appropriate avidity to peptide–MHC complexes (pMHC) presented on cortical thymic epithelial cells to become mature thymocytes (Sawicka et al., 2014). Depending on the specificity of clonal TCR to MHC class I (MHC-I) or MHC class II (MHC-II), selected thymocytes differentiate into the CD8+ cytotoxic or CD4+ helper lineage, respectively. The selected mature thymocytes keep only one of the two coreceptors with the other repressed or permanently silenced at the transcriptional level. The specificity of TCR to MHC-I versus MHC-II, differentiation to the helper versus cytotoxic lineage, and the choice of coreceptor expression are all tightly linked.
This tight link makes the study of the regulation of CD4 and CD8 coreceptor expression unique and superb not only from the viewpoint of immunology but also from that of gene regulation. From the immunology aspect, helper and cytotoxic T-cell responses to TCR stimulation are distinct and the two cell types play nonredundant roles in immune responses, even though they are derived from a common precursor pool of DP thymocytes. Cytotoxic T cells are professional effectors to kill target cells, such as virally infected cells and cancer cells. Following activation through interaction with antigen-presenting dendritic cells, cytotoxic T cells undergo massive proliferation and produce IFN-γ and TNF. Ubiquitous expression of MHC-I allows cytotoxic T cells expressing CD8 and MHC-I-restricted TCR to recognize and kill a wide variety of cells that are infected by intracellular pathogens or transformed. In contrast, helper T cells that express MHC-II-restricted TCR and the CD4 coreceptor are functionally diverse and plastic. Activated helper T cells regulate cytotoxic T-cell responses, B-cell responses, and innate responses through production of various cytokines, depending on priming cytokine milieu provided by innate immune cells.
Such distinct properties of helper and cytotoxic T cells are programmed during a brief time window of thymic positive selection, in which continued expression or transcriptional repression of the CD4 or CD8 coreceptor is specifically determined. Because the helper versus cytotoxic lineage decision during positive selection is largely irreversible, it is reasonable to speculate that positive selection signals establish self-sustainable or imprinted genetic circuitry that establishes identities of helper and cytotoxic lineage cells. CD4 and CD8 coreceptors are not only markers for the distinct lineages of T cells. These molecules are involved in the initiation of the development of helper and cytotoxic T cells during positive selection, and continued expression of the same coreceptor used in the selection is essential for the functions of each subset. Therefore, it is possible that common genetic circuitry regulates the lineage identities and stable coreceptor expression in postselection thymocytes and mature T cells in the periphery. At the same time, mature SP thymocytes and T cells shut off expression of the coreceptor that is not associated with their TCR specificity to MHC. While CD8 repression in CD4+ T cells appears reversible, CD4 silencing in CD8+ T cells seems nearly irreversible and maintenance of the silencing by epigenetic mechanisms is implicated. While epigenetic gene silencing is an important mechanism to maintain stable gene expression signature in many cell types, the molecular mechanisms by which a gene is initially repressed by a transacting factor- and cis-element-dependent manner and subsequently becomes “epigenetically silenced” independent of the triggering transacting factors or its target cis-elements are poorly understood. From this point, study of Cd4 silencing serves as an excellent model system.
In this chapter, I will first summarize recent advances in genetic and epigenetic regulation of genes encoding CD4 and CD8 coreceptors and then discuss the roles of transcription factors in the regulation of coreceptor expression and helper versus cytotoxic lineage decisions.
2 CD4 and CD8 Coreceptors and Thymocyte Selection
2.1 Molecular timers defining the duration of positive selection signals
Based on the tight links between TCR specificity to MHC and coreceptor expression, several different models have been proposed to explain how positive selection signals regulate the helper versus cytotoxic lineage decision and experimentally validated. Two major classical models are the instructive model and the stochastic model. The instructive model proposed that the strength of positive selection signals resulting from different affinity of CD4 and CD8 cytoplasmic tails to the Src family tyrosine kinase Lck determines the outcome of the lineage choice of selected DP thymocytes (Hernandez-Hoyos, Sohn, Rothenberg, & Alberola-Ila, 2000; Itano et al., 1996; Seong, Chamberlain, & Parnes, 1992; Sohn, Forbush, Pan, & Perlmutter, 2001; Wiest et al., 1993). However, subsequent genetic studies using Lck-noninteracting CD4 demonstrated that CD4–Lck interactions are not absolutely essential for the helper lineage development (Killeen & Littman, 1993). Therefore, instructive signals, if any, are likely to be Lck-independent. Subsequent studies tested other...
Erscheint lt. Verlag | 12.1.2015 |
---|---|
Mitarbeit |
Herausgeber (Serie): Frederick W. Alt |
Sprache | englisch |
Themenwelt | Medizin / Pharmazie ► Allgemeines / Lexika |
Medizin / Pharmazie ► Medizinische Fachgebiete | |
Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
ISBN-10 | 0-12-802431-3 / 0128024313 |
ISBN-13 | 978-0-12-802431-7 / 9780128024317 |
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