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TH17 AND TREG CELLS IN AUTOIMMUNITY
Won-Woo Lee Laboratory of Autoimmune and Inflammation (LAI) Department of Microbiology and Immunology Seoul National University College of Medicine
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Overview The making and breaking of self-tolerance Regulatory T cells
Th17 T cells Pathogenic roles of Th17/Treg in autoimmune diseases 2
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Need to generate a state of self-tolerance
3 The making and breaking of self-tolerance Lymphocytes randomly generate the antigen receptors in central lymphoid organs and this process inevitably results in the generation of some lymphocytes with affinity for self antigens Need to generate a state of self-tolerance
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Discrimination of self and non-self
4 The making and breaking of self-tolerance Discrimination of self and non-self Mechanism Self antigens Non-self antigens Antigen receptor signaling Immature lymphocytes In central lymphoid organs (Induction of central tolerance) Mature lymphocytes In peripheral lymphoid organs Antigen concentration Continuous and high Sudden and rapid increase of previously low concentrated antigen Co-stimulatory signals absent present But it is not easy to achieve! How does a lymphocyte know what “self” really is?
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Layers of self-tolerance
5 The making and breaking of self-tolerance Layers of self-tolerance Self-tolerance depends on the concerted action of a variety of mechanisms that operate at different sites and stages of development A Succession of checkpoints Peripheral tolerance
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The making and breaking of self-tolerance
6 The making and breaking of self-tolerance TCR signal strength instructs CD4+ thymocyte fate and Treg cell differentiation Central tolerance Nature Treg cells CD4 T cells Josefowicz SZ et al. Annu Rev Immunol. 2012;30:531-64
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Impaired Treg cell-mediated suppression in autoimmunity
7 The making and breaking of self-tolerance Impaired Treg cell-mediated suppression in autoimmunity Failures Jane Hoyt Buckner Nature Rev Immunol 2010
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Activation of ignorant lymphocytes
8 The making and breaking of self-tolerance Activation of ignorant lymphocytes Most circulating lymphocytes are “ignorant” of self but functional to foreign agents. No response to self antigen under normal circumstances Unfortunately, ignorant lymphocytes are potentially self reactive under certain circumstances Inflammation and infection Co-stimulation through TLRs ->Toll hypothesis (e.g. SLE) Exogenous or endogenous ligands for TLRs Changing the availability or form of a self antigens Immune complexes with formation of multivalence (e.g. RF) Ignorance: An important mechanism Lymphocytes with low affinity for self-antigen, can go to the periphery and encounter the self-antigen but can avoid becoming activated by They remain ignorant, of self but functional to foreign agents Unfortunately, ignorance can be overcome by strong stimulus like major infection or tissue damage and can lead to autoimmune reactions
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Allergic or Hypersenstivity
9 The making and breaking of self-tolerance The importance of immune regulation Normal immune homeostasis involves a balance between T cells, B cells, and antibodies that are reactive with self, non-self, or both Non-self-reactivity Self-reactivity Normal immune Homeostasis Allergic or Hypersenstivity disease Autoimmune Immune deficiency Modified from Jennette JC et al. Kidney Int 9
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Develop when multiple layers of self-tolerance are dysfunctional
10 The making and breaking of self-tolerance Autoimmune diseases Develop when multiple layers of self-tolerance are dysfunctional Response to endogenous self antigen that leads to tissue damage Response is sustained since self antigen cannot be eliminated A combination of genetic susceptibility, break down of natural tolerance mechanism and environmental triggers
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Requirements for the development of autoimmune diseases
11 The making and breaking of self-tolerance Requirements for the development of autoimmune diseases Single-gene mutations (AIRE, CTLA4, Foxp3) Association of HLA alleles (B27, DR2, DR3, DR3/4) Polymorphism in non-HLA genetic associations (PTPN22, IL-23R, NOD2) Heterogeneous geographic distribution Infectious agents Trauma Drugs Hormone (estrogen, progesterone) Imbalance between lymphocyte activation and control mechanisms. Systemic or organ specific Chronic, progressive, and self-perpetuating
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The making and breaking of self-tolerance
12 The making and breaking of self-tolerance Postulated mechanisms of autoimmunity
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Regulatory T cells Suppressor T cells
13 Regulatory T cells Suppressor T cells : 다른 종류의 세포 활성에 영향을 줌으로서 면역기능을 억제하는 세포군 대부분의 biologic system들이 복잡한 regulatory controls 하에 놓여 있는 것을 볼 때 면역계도 예외 일 수 없다. 면역계의 특성을 고려할 때 robust 한 immune responses로 pathogen을 제거한 후에는 이러한 potentially harmful한 반응의 강도를 조절하면서 최종적으로 끝낼 수 있는 기전이 존재해야 할 것이다. 말초에는 항상 potentially autoreactive한 T 세포가 존재하고 있기 때문에 이를 제어할 수 있는 “active”한 기전이 존재해야 할 것이다.
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Regulatory T cells Historical perspective
14 Regulatory T cells Historical perspective Gershon and Kondo’s experiments (1970): “High-zone” tolerance Supraoptimal dose의 SRBCs를 항원으로 주입하고 동일항원으로 challenge하는 경우 specific tolerance 혹은 nonresponsiveness가 나타나는 현상 관찰 Gershon and Kondo’s experiments 2. Bewildering I-J episode The existence of CD8 suppressor T cells expressing I-J molecules were proposed No existence of the I-J region and no definitive evidence for anomaly of suppressor T cells in autoimmune diseases.
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Regulatory T cells 3. Nishizuka and Sakakura’s experiments (1969)
15 Regulatory T cells 3. Nishizuka and Sakakura’s experiments (1969) 생쥐에서 생후 3일째 흉선을 제거한 경우 organ-specific autoimmunity가 유발된다. 4. Penhale’s experiments (1973) 쥐에서 생후 3-5주에서 흉선을 제거하고 2주에 한번씩 sublethal X-irradiation을 4차례 반복하면 자가면역성 갑상선염이 발생함. Sakaguchi S et al. Eur. J. Immunol. 2007
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Regulatory T cells Timeline: Treg cell discovery 16
Sakaguchi S et al. Nat. Rev Immunol. 2010
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Sakaguchi S et al. J Immunol. 1995
17 Regulatory T cells Definition of regulatory T cells CD4 CD25 CD25 Sakaguchi S et al. J Immunol. 1995 IL-7Rα CD4+CD25highIL-7Ralow Liu W et al. J. Exp. Med. 2006 Seddiki N et al. J. Exp. Med. 2006
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18 Regulatory T cells Differentiation dynamics of FoxP3 expressing CD4+ T cells Miyara M et al. Autoimmun Rev. 2011
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Delineation of FoxP3+CD4+ T Cells into Subsets
19 Regulatory T cells Delineation of FoxP3 expressing CD4+ T cells Delineation of FoxP3+CD4+ T Cells into Subsets T cell subpopulations delineated by CD25, Foxp3, and the Treg-cell-type epigenome CD4+CD25highIL-7Ralow Ohkura N et al. Immunity 2013 Miyara M et al. Immunity. 2009
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Grant CR et al. Autoimmun Rev. 2014
Regulatory T cells Regulatory T cell mechanisms of suppression Modulation of antigen presenting cell maturation and function Killing of target cells Disruption of metabolic pathways Production of anti-inflammatory cytokines Sakaguchi S et al. Nat. Rev Immunol. 2010 Grant CR et al. Autoimmun Rev. 2014
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Regulatory T cells Clinical application of regulatory T cells 21
Miyara M et al. Nat Rev Rheumatol. 2014 Sakaguchi S et al. Nat. Rev Immunol. 2010
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Roles of Th17 cells in autoimmune diseases
22 Roles of Th17 cells in autoimmune diseases Th1/Th2 paradigm (1986년) Are B cell help and delayed-type hypersensitivity mediated by different types of CD4+ Th cells? Humoral immunity & allergy Cellular immunity 22 22
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Flaws in predictions from the Th1/Th2 hypothesis and outcomes in EAE
23 Roles of Th17 cells in autoimmune diseases Th2 Th1 IFN-g ↑ TNF ↑ in EAE Flaws in predictions from the Th1/Th2 hypothesis and outcomes in EAE Prediction Outcome Administration of g-IFN would worsen EAE Administration of g-IFN protected from EAE g-IFN knockouts would be resistant to EAE EAE worse in g-IFN knockouts Antibody to g-IFN would protect in EAE Antibody to g-IFN worsened EAE TNF knockouts would be resistant to EAE TNF knockouts had worsened EAE Administration of TNF would worsen EAE Administration of TNF protected from EAE Steinman L Nat. Med. 2007 23
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Day after immunization
24 Roles of Th17 cells in autoimmune diseases A challenge to the Th1/Th2 paradigm IL-23p19 KO, but not IL-12p35 KO, mice were shown to be resistant to CIA and EAE. IL-12p35-/- (IL12-/- ) B6 WT IL-23p19+/- EAE clinical grade IL-12p40-/- (IL12-/- and IL-23-/-) IL-23p19-/- Day after immunization Cua DJ et al. Nature 2003 24 24
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Roles of Th17 cells in autoimmune diseases
25 Roles of Th17 cells in autoimmune diseases A challenge to the Th1/Th2 paradigm IL-23 expands/generates IL-17-producing T cells that are pathogenic in autoimmunity. DLN CD4 T cells CNS infiltrating CD4+ cells (D7) WT IL-23p19-/- Isotype IFN-γ IL-17 CD4 Langrish CL et al. J Exp Med 2005 On the basis of these findings, investigators proposed that IL-17-producing T cells are distinct T helper cell subset (Th17), which was critical for pathogenesis in autoimmune diseases. 25 25
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Seminal findings in IL-17 and Th17 cell biology
26 Roles of Th17 cells in autoimmune diseases Seminal findings in IL-17 and Th17 cell biology Gaffen SL Nat Rev Immunol. 2009 26 26
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“Three signals” are required for antigen-specific T cell activation.
27 Roles of Th17 cells in autoimmune diseases “Three signals” are required for antigen-specific T cell activation. Activation Survival Differentiation 27
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Immunity to extracellular parasites. Allergy
28 Roles of Th17 cells in autoimmune diseases Signaturereceptors IL-12Rβ2 IL-18R IL-23R IL-1R (?) IL-2Rα (CD25) ? IL-21R IL-4R Major TFs STAT1 STAT4 T-bet RORgt RORα STAT3 FOXP3 IRF4 (?) BCL6 c-MAF STAT6 GATA3 Signaturecytokines IFN-g TNF IL-17A/F IL-21 IL-22 IL-26 TGF-β IL-10 IL-9 IL-4 IL-5 IL-13 Biological functions Immunity to viruses, intracellular bacterial and parasites. Autoimmunity Immunity to extracellular bacterial and fungal infections. Autoimmunity Regulation, tolerance Immunity to parasites T cell help for B cells Immunity to extracellular parasites. Allergy Th1 iTreg Th17 TGF-b, IL-6 TGF-b IL-12 Naive CD4+ TFH Th9 IL-4, TGF-b IL-6, IL-21 IL-4 Th2
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Roles of Th17 cells in autoimmune diseases
29 Roles of Th17 cells in autoimmune diseases TGF-b and IL-6 is critical cytokines for Th17 cell differentiation IL-17 IFN-g Veldhoen M et al Immunity 2006
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Roles of Th17 cells in autoimmune diseases
30 Roles of Th17 cells in autoimmune diseases RORgt is a major transcriptional factor for Th17 cell differentiation EGFP-retroviral vector Ivanov II et al Cell 2006
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Th17-cell mediated host immunity
31 Roles of Th17 cells in autoimmune diseases Th17-cell mediated host immunity Gaffen SL, Cytokines 2008
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Roles of Th17 cells in autoimmune diseases
32 Roles of Th17 cells in autoimmune diseases Onishi RM et al Immunology 2010
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Roles of Th17 cells in autoimmune diseases
33 Roles of Th17 cells in autoimmune diseases Pathogenic role for IL-17 in SLE IFN-g % of IL-17+ cells (CD3+CD8- cells) Yang J et al, Arthritis Rheum. 2009 IL-17 IL-17+/IFN-g- IL-17+/IFN-g+ IL-17-/IFN-g+ Shah K et al, Arthritis Res Ther. 2010 Patients with SLE had an increased frequency of CD4+IL-17+ T cells but not CD4+IFN-γ+ T cells compared with healthy subjects. 33
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Roles of Th17 cells in autoimmune diseases
34 Roles of Th17 cells in autoimmune diseases Pathogenic role for IL-17 in Psoriasis Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human Th17 cells that promote the production of antimicrobial peptides in human keratinocytes. b-defensin Wilson NJ et al, Nat Immunol 2007 34
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Th17 cell differentiation
35 Roles of Th17 cells in autoimmune diseases Th17 cell differentiation Signal 1&2 IL-23R IL-1Rs (human, mouse?) CD161(human) TGF-b, IL-6, IL-21, IL-23, IL-1b (human) IFN-g, IL-4, IL-25, IL-27 RA, VitD, IL-2 IL-17A, IL-17F, IL-21, IL-22, TNF, CCL20, IL-26 (human) iTreg
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Pathogenic roles of Th17/Treg in autoimmune diseases
36 Pathogenic roles of Th17/Treg in autoimmune diseases “Identity Crisis” Retinoic acid Identity crisis of Th17 cells: Many forms, many functions, many questions The balance between Treg and Th17 cells The plasticity of Th17 Pathogenic vs. nonpathogenic Th17 cells
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The reciprocal relationship between iTreg and Th17 cells
37 Pathogenic roles of Th17/Treg in autoimmune diseases The reciprocal relationship between iTreg and Th17 cells Pan F et al. Science Signaling 2010
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The reciprocal relationship between iTreg and Th17 cells
38 Pathogenic roles of Th17/Treg in autoimmune diseases The reciprocal relationship between iTreg and Th17 cells Pasare C and Medzhitov R Science 2003 Bettelli E et al Nature 2006 “Toll pathway–dependent blockade of CD4+CD25+ T cell–mediated suppression by dendritic cells”
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Reciprocal expression of Foxp3 and IL-17
39 Pathogenic roles of Th17/Treg in autoimmune diseases Reciprocal expression of Foxp3 and IL-17 Foxp3-GFP knockin mice Bettelli E et al Nature 2006
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Pathogenic roles of Th17/Treg in autoimmune diseases
40 Pathogenic roles of Th17/Treg in autoimmune diseases Th17 cells Naive CD4 T cells Foxp3 IL-17 Treg Zhang F et al Nat Immunol 2008
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The reciprocal relationship between iTreg and Th17 cells
41 Pathogenic roles of Th17/Treg in autoimmune diseases The reciprocal relationship between iTreg and Th17 cells Kunisawa J et al. Front. Immunol., 2013 Daniel Mucida D et al, Science, 2007
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The reciprocal relationship between iTreg and Th17 cells
42 Pathogenic roles of Th17/Treg in autoimmune diseases The reciprocal relationship between iTreg and Th17 cells A. Jager et al. Scand J Immunol. 2010 AhR: Aryl hydrocarbon receptor (ligand-dependent TF) / FICZ: 6-formylindolo[3,2-b]carbazole: an endogenous ligand with high affinity for the AHR receptor / TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin
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The reciprocal relationship between iTreg and Th17 cells
43 Pathogenic roles of Th17/Treg in autoimmune diseases The reciprocal relationship between iTreg and Th17 cells Eric V. Dang EV et al. Cell 2011
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Tregs, Th17, and IL-17+Foxp3+ T cells interact with each other
44 Pathogenic roles of Th17/Treg in autoimmune diseases Tregs, Th17, and IL-17+Foxp3+ T cells interact with each other Du R. et al . Journal of Leukocyte Biology 2014
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Pathogenic roles of Th17/Treg in autoimmune diseases
45 Pathogenic roles of Th17/Treg in autoimmune diseases Transitions of CD4+ T cell subsets Murphy KM et al Nat Immunol 2010 45 45
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Reinforcement and destabilization of CD4+ T cell subsets.
46 Pathogenic roles of Th17/Treg in autoimmune diseases Reinforcement and destabilization of CD4+ T cell subsets. Th1 Th2 Th17 iTreg Murphy KM et al Nat Immunol 2010 46 46
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Pathogenic roles of Th17/Treg in autoimmune diseases
47 Pathogenic roles of Th17/Treg in autoimmune diseases Retinoic acid Markus Kleinewietfeld M et al. Seminars in Immunology 2013
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“IL-1 watches the watchmen”
48 Pathogenic roles of Th17/Treg in autoimmune diseases “IL-1 watches the watchmen” Published online 2 February 2015; doi: /ni.3099 Retinoic acid Villarino AV et al. Nat. Immunol 2015
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Pathogenic roles of Th17/Treg in autoimmune diseases
49 Pathogenic roles of Th17/Treg in autoimmune diseases : Comparisons of the transcriptional profiles of pre- and post conversion TH17 cells also revealed a role for canonical TGF-b signaling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. : Novel mechanisms for differentiation of stable subsets of TH17 cells endowed with different inflammatory capacity as well as factors that modulate their effector function
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Pathogenic roles of Th17/Treg in autoimmune diseases
50 Pathogenic roles of Th17/Treg in autoimmune diseases 50
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Pathogenic roles of Th17/Treg in autoimmune diseases
51 Pathogenic roles of Th17/Treg in autoimmune diseases VOLUME 20 | NUMBER 1 | JANUARY 2014 nature medicine
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