T Regulatory Cells in Human Health and Diseases

Contents
Contributors
Chapter 1: Regulatory T Cells: Concept, Classification, Phenotype, and Biological Characteristics
	1.1 Introduction
	1.2 Treg and the Immune Response
	1.3 Classification of Treg Cells
	1.4 CD4+Foxp3+ Treg Cells
	1.5 Tr1 Cells
	1.6 CD8+ Treg Cells
		1.6.1 CD8+CD103+ Treg Cells
		1.6.2 CD8+CD122+ Treg Cells
		1.6.3 CD8+CD28- Cells
		1.6.4 CD8+ Qa-1-Restricted CD8αα+TCRαβ+ Regulatory T Cell
	1.7 Similarity and Differences Between tTreg and iTreg Cells
	1.8 Treg in Diseases
		1.8.1 Treg in Autoimmune Diseases
		1.8.2 Tregs in Infectious Diseases
		1.8.3 Treg in Cancer
		1.8.4 Treg in Organ Transplantation
	1.9 Conclusion
	References
Chapter 2: A Structure-Guided Delineation of FOXP3 Regulation Mechanism in IPEX
	2.1 Treg Cells Play a Central Role in Peripheral Immune Tolerance
	2.2 Foxp3 Is the Dominant Regulator of Treg Cell Lineage Commitment and Maintenance
	2.3 Structural Features of Foxp3 Protein
	2.4 Foxp3 Activity Is Modified by Protein Posttranslational Modifications and Interactions
	2.5 Conclusion
	References
Chapter 3: Regulation of Treg Functions by the Ubiquitin Pathway
	3.1 Introduction
	3.2 The Ubiquitination Pathway
	3.3 Regulation of Treg Function by E3 Ligases Directly Targeting FoxP3
	3.4 Stub 1 Potentiates Environmental Cues to Regulate Treg Function
	3.5 TRAF6 Controls FoxP3 Localization Via K63 Ubiquitination
	3.6 Cbl-b Induces FoxP3 Degradation Upon TCR/CD28 Stimulation
	3.7 UBC13, a Critical E2 in Treg Functions
	3.8 Indirect FoxP3 Targeting Through Ubiquitination
	3.9 RNF20 Decreases FoxP3 Transcription Through H2B Ubiquitination
	3.10 Hrd1 Destabilizes FoxP3 Through an Inflammation-Induced ER Stress Response
	3.11 HIF-1, an Important VHL in FoxP3 Stability
	3.12 ITCH Deficiency Results in Th2-Like Treg Cells
	3.13 GRAIL Restrains Inappropriate Gene Expression in Tregs
	3.14 DUBs of FoxP3 in Regulating Treg Functions
	3.15 USP22 Functions as Both a Transcriptional and Posttranslational Regulator of FoxP3
	3.16 USP21 Prevents Generation of Th1-Like Treg Cells
	3.17 USP7 Inhibition Results in Severe Treg Instability
	3.18 Dysregulation of Treg Ubiquitin Pathway in Human Diseases
	3.19 Conclusion and Perspectives
	References
Chapter 4: Ubiquitin-Dependent Regulation of Treg Function and Plasticity
	4.1 Introduction
	4.2 A Brief History About Regulatory T Cells and Foxp3
	4.3 Natural Regulatory T (nTreg) and Induced Regulatory T (iTreg) Cells
	4.4 Mechanisms of Ubiquitin-Dependent Regulation
	4.5 Ubiquitin-Dependent Regulation of Treg Function
		4.5.1 Itch
		4.5.2 Ubc13
		4.5.3 Stub1
	4.6 Ubiquitin-Dependent Regulation of Treg Plasticity
		4.6.1 Cbl-b
		4.6.2 TRAF6
		4.6.3 RNF31
		4.6.4 A20
	4.7 Deubiquitinases: The Janus of Ubiquitin-Dependent Regulation
		4.7.1 USP7
		4.7.2 USP21
		4.7.3 USP44
	4.8 Concluding Remarks
		4.8.1 HIF-1
		4.8.2 YAP/Mst1/Mst2 from Hippo Signaling Pathway
		4.8.3 Clinical Implication
	References
Chapter 5: Metabolic Choice Tunes Foxp3+ Regulatory T Cell Function
	5.1 Introduction
	5.2 Treg Cell Metabolism State and Function
		Box 5.1: Amino acids not only supply for protein synthesis but also can meet the other requirements for cellular immune functi...
	5.3 Cellular Metabolism, Epigenetic Regulation, and Treg Cells Function
	5.4 Conclusion
	References
Chapter 6: Treg Cells and Epigenetic Regulation
	6.1 Introduction
	6.2 Treg Cell Differentiation and Epigenetics
		6.2.1 Definition of Epigenetics
		6.2.2 Three Mechanisms of Epigenetics
		6.2.3 Immunologic Balance: The Balance of Pro-versus Anti-inflammatory Cytokines
		6.2.4 The Two Major Pathways of T-Cell Differentiation: The CD4+ T Helper (Th) and the CD8+ T Cytotoxic (Tc) Populations
		6.2.5 Cytokines Produced Following CD4+ T-Cell Differentiation
		6.2.6 Molecular Mechanisms of Treg Cells in Immune Regulation
	6.3 The Role of Commensal Bacteria in Shaping the Immune Response Through Epigenetic Mechanisms
		6.3.1 Local Gut Immune Responses
		6.3.2 Classification and Function of Microbe-Induced CD4+ Treg in the Gut
		6.3.3 Mechanism(s) of Induction of Gut CD4+ Treg Cells by Commensal Microbiota
		6.3.4 Role of Anaerobic Microbes in Shaping Gut Immune Responses
	6.4 Studies from Our Own Laboratory
		6.4.1 In Vitro Induction of T Regulatory Cells by a Methylated CpG DNA Sequence in Humans: Potential Therapeutic Applications ...
		6.4.2 Studies of the Treg-Inducing Capacity of DNA from Bifidobacterium longum subsp. infantis and Lactobacillus rhamnosus: Im...
	6.5 Prospective Clinical Applications of Treg Cells and Epigenetic Regulation
	References
Chapter 7: TCR/ITK Signaling in Type 1 Regulatory T cells
	7.1 Introduction
	7.2 Structure of ITK
	7.3 TCR/ITK Signaling Pathway
	7.4 Kinase-Independent ITK Function
	7.5 Function of ITK in T Helper Cell Designation
	7.6 TCR/ITKRas/MAPK/IRF4 Pathway in Tr1 Cells
	7.7 Conclusions
	References
Chapter 8: Adipose Tissue T Regulatory Cells: Implications for Health and Disease
	8.1 Introduction
	8.2 Adipocytes at the Crossroads of Immunity and Metabolism
	8.3 Tregs Help Maintain Adipose Tissue Homeostasis
	8.4 Adipocytes and Macrophages Contribute to the Loss of at Tregs in Obesity: Implications for Systemic Metabolism
	8.5 Regulation of Treg Differentiation and Function: Key Factors in VAT
	8.6 A Distinct Phenotype of AT Tregs
	References
Chapter 9: Intestinal Regulatory T Cells
	9.1 Introduction to Intestinal Tregs
	9.2 Intestinal Tregs Subsets
		9.2.1 Thymic vs. Peripheral Tregs
		9.2.2 GATA3+Helios+(Nrp1+) Tregs
		9.2.3 RORγt+Helios- pTregs
		9.2.4 RORγt- Nrp1-(Helios-) pTregs
		9.2.5 Effector Tregs and IL10+ Tregs
	9.3 Antigen Specificity of Intestinal Tregs
	9.4 Key Factors Required for the Development and Maintenance of Tregs in the Gut
		9.4.1 Host Factors: Cytokines
		9.4.2 Host Factors: TNFRSF-NF-κB Axis
		9.4.3 Environmental Factors: Commensal Microbiota
		9.4.4 Environmental Factors: Dietary and Microbial Metabolites
	9.5 Suppressive Function Mediated by Treg in the Gut
		9.5.1 Secretion of Inhibitory Cytokines
		9.5.2 Expression of Cell Surface Inhibitors of Inflammation
			9.5.2.1 Contact-Dependent Inhibition
			9.5.2.2 Contact-Independent Inhibition
		9.5.3 Cytolysis
	9.6 Treg During Intestinal Diseases
		9.6.1 Inflammatory Bowel Disease
		9.6.2 Celiac Disease
		9.6.3 Necrotizing Enterocolitis
		9.6.4 Graft-Versus-Host Disease (GVHD)
		9.6.5 Tregs in Colorectal Cancer
	9.7 Treg-Related Therapeutic Approaches
		9.7.1 Treg Infusion
		9.7.2 Promoting the Number and Function of Endogenous Tregs
			9.7.2.1 Targeting Cytokines and Inflammatory Pathways
			9.7.2.2 Mesenchymal Stem Cell (MSC) Infusion
			9.7.2.3 Induction of Tregs by Microbiota
			9.7.2.4 Dietary Vitamins
	9.8 Conclusions
	References
Chapter 10: The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases
	10.1 Tregs Are Shaped by the Gut Microbiota
	10.2 Gut Dysbiosis-Related Autoimmune Disorders Involve Tregs
		10.2.1 Monogenic Primary Autoimmune Disorders Related to Tregs Are Associated with Gut Microbial Dysbiosis
		10.2.2 Polygenic Autoimmune Diseases with Treg Dysfunction Are Associated with Gut Microbial Dysbiosis
		10.2.3 Autoimmune Diseases in the Central Nervous System (CNS)
		10.2.4 Gastrointestinal Autoimmune Disorders
	10.3 Resetting Microbiota and Tregs in Diseases
	References
Chapter 11: Tregs in Autoimmune Uveitis
	11.1 Introduction
	11.2 Foxp3 and Tregs
	11.3 Tregs Development and Maintenance
	11.4 Tregs in Clinic Patients with Uveitis
	11.5 The Role of Tregs in the EAU
	11.6 Tregs-Related Drug Therapy in the EAU Model
	11.7 Tregs Therapy in EAU Model
	11.8 Conclusion
	References
Chapter 12: Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy
	12.1 Introduction
	12.2 Tregs in Cancer
		12.2.1 Cellular Source of Tumor-Infiltrating Tregs
		12.2.2 Chemokine Receptors in Tumor-Infiltrating Tregs
		12.2.3 Mechanisms of Action (Summarized in Fig. 12.1)
	12.3 Targeting Tregs for Cancer Immunotherapy
		12.3.1 Immune Checkpoints as Therapeutic Targets for Tregs
			12.3.1.1 Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4)
			12.3.1.2 Lymphocyte-Activation Gene 3 (LAG-3, CD223)
			12.3.1.3 T-Cell Immunoreceptor with Ig and ITIM Domains (TIGIT)
			12.3.1.4 T-Cell Immunoglobulin and Mucin-Domain Containing-3 (TIM-3)
			12.3.1.5 Programmed Cell Death-1 (PD-1)
		12.3.2 Co-stimulatory Receptors as Therapeutic Targets for Tregs
		12.3.3 Chemokine Receptors as Potential Therapeutic Targets for Tregs
			12.3.3.1 CCR4
			12.3.3.2 CCR5
			12.3.3.3 CCR8
		12.3.4 Other Targets for Tumor-Infiltrating Tregs
	12.4 Perspectives
	References
Chapter 13: TNF-TNFR2 Signal Plays a Decisive Role in the Activation of CD4+Foxp3+ Regulatory T Cells: Implications in the Tre...
	13.1 Introduction
	13.2 Biology of Tumor Necrosis Factor and Its Receptors
		13.2.1 Tumor Necrosis Factor
		13.2.2 Tumor Necrosis Factor Receptors
		13.2.3 TNF-TNFRs Signal Transduction
	13.3 The Decisive Role of TNF-TNFR2 Interaction in the Activation of Tregs
	13.4 Activation of Tregs Through TNFR2 in the Treatment of Inflammatory Diseases
	13.5 Elimination of Tregs Activity Through Blockade of TNFR2 Signal in Cancer Immunotherapy
	13.6 Conclusion
	References
Chapter 14: The Pursuit of Regulatory T Cells in the Induction of Transplant Tolerance
	14.1 Introduction
	14.2 Transplant Rejection and the Unique Roles of Tregs
		14.2.1 Features of Transplant Rejection
		14.2.2 Tregs in Transplant Survival
	14.3 Clinical Trials Involving Tregs as Cellular Therapeutics
		14.3.1 Production of Tregs Ex Vivo
		14.3.2 The Impact of Immunosuppression Drugs on Treg Functions
		14.3.3 Clinical Trials Utilizing Tregs in Transplantation
	14.4 Ongoing Clinical Trials
	14.5 Conclusions
	References
Chapter 15: Regulatory T Cells for the Induction of Transplantation Tolerance
	15.1 Introduction
	15.2 Phenotype and Heterogeneity
	15.3 Mechanisms of Treg in Underlying Transplantation Tolerance
	15.4 The Role Treg Cells in Preclinical Transplantation Models
	15.5 The Role of Treg Cells in Clinical Transplantation Trials
		15.5.1 Isolation
		15.5.2 Expansion
		15.5.3 Timing
		15.5.4 Dosing
		15.5.5 Quality Control
		15.5.6 Genetically Modified Tregs
		15.5.7 Concomitant Immunosuppressants
		15.5.8 Post-administration Monitoring
	15.6 Conclusion
	References