RORγt and IL-17 Responses`
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1 Falk Workshop Mechanisms of Intestinal Inflammation October 10, 2007 and IL-17 Responses` Dan Littman HHMI, Skirball Institute New York University School of Medicine
2 New paradigm for T Helper Cell Differentiation T H 1 T-bet IFN-γ Kill intracellular pathogens IL-12 IL-23 IL-27 Naive IL-6 + IL-2 T H 17 IL-17 IL-17F IL-22 Extracellular pathogens (e.g. Klebsiella, Citrobacter) Tissue repair, angiogenesis? Autoimmune inflammation (e.g. EAE, CIA, IBD) IL-4 T H 2 GATA3 IL-4 IL-10 IL-5 IL-13 Extracellular pathogens Allergy, asthma
3 RORα Ligand Binding Domain Retinoic Acid Receptor (RAR) - Related Orphan Nuclear Receptor Kallen et al., 2004
4 Regulation of Nuclear Receptor Activity Perissi & Rosenfeld, Nature Reviews Molecular Cell Biology 6, (2005)
5 Ch. 3 Products of the Rorc Locus 1γ 2γ 1γt 3-4γ/γt Pγ? ATG Pγt? ATG liver, muscle; circadian regulation RORγ LK DBD LBD AF2 LK Lymphoid lineage cells in the immune system: DP thymocytes; LTi cells; Th17 cells
6 Functions of in the immune system Thymocyte selection: promotes survival of CD4 + CD8 + cells, essential for inkt cell development Lymphoid organogenesis: required for development of cells that induce differentiation of secondary lymphoid organs and tertiary intestinal lymphoid aggregates Th17 cell differentiation: specifies the program of these cells in the small intestine and in inflammatory diseases
7 Targeting of the Rorγt locus with GFP 1γ 2γ 1γt 3-4γ/γt ATG EGFP neo Eberl et al. Nat. Immunol. 2004
8 Cryptopatch in the small intestine LTi Cell ( gfp/+ ) DC B Cell
9 (GFP) + T cells in small intestine express IL-17 GFP- GFP No stimulation h acd3/ acd28 TCRβ GFP () IL Ivanov et al., 2006
10 and T H 17 cells In mice bred in SPF facility, IL-17 is constitutively expressed (only) in CD4 + T cells in the intestine and lung, and requires IL-6-mediated induction of (and IL-23?) IL-6 and independently induce some, but alone do not induce IL-17 in naïve CD4 + T cells The hallmark cytokines and chemokine receptors in the Th17 program (IL-17, IL-17F, IL-22, CCR6) are induced in TCR-activated T cells upon forced expression of T H 17 cells cannot be induced by IL-6 plus TGFβ in naïve CD4 + T cells from -deficient mice Does attenuation of activity in T cells reduce the severity of autoimmune disease?
11 Reduced Severity of MOG-Induced EAE in the Absence of 6 Score KO (N=6) WT (N=6) RAG (N=3) 2 1 * * * ** ** *** Day * p < 0.05 ** p < ***p < ttest Ivanov et al., 2006
12 EAE: Reduction in IL-17 + T Cells in CNS of RORγ KO Mice WT (score 2) Rorγ -/- (score 2) Rorγ -/- (score 0) IFNγ IL %CD4 + IL ** WT Rorγ -/- ** Total IFNγ + IFNγ - * %CD4 + IFNγ Ivanov et al., 2006
13 is required for disease in two murine autoimmunity models: EAE and transfermediated IBD IL-17 is elevated locally in several human autoimmune and inflammatory diseases Blockade of function may reduce inflammation in human autoimmune disease
14 Why is IL-23 required in vivo, but not in vitro, for the differentiation of T H 17 cells?
15 IL-6 Induces IL-21 and IL-23R in CD4+ T Cells IL-21 mrna IL IL IL IL IL-23R mrna nd nd nd nd Rorγt gfp/gfp Rorγt +/+
16 Family of γ c Chain Receptors Stat3 Stat1 Stat5A Stat5B
17 IL-21 Contributes to Th17 Cell Differentiation IL-17F None IL-6+ IL Il21r +/ Il21r -/ IL-17 IL-23R mrna IL IL Il21r +/+ Il21r -/- nd nd nd nd L. Zhou, R. Spolski, W. Leonard
18 Defective induction of IL-17 + T cells in the absence of IL-21R Gated on CD4 + TCRβ + lymph node cells Il21r +/+ Il21r +/+ Il21r -/- Il21r -/ IFNγ IL-17 Draining LN in RAG ko mice at day 11 after transfer of WT or IL-21R -/- CD4 + T cells and immunization with Ova/CFA I. Ivanov, R. Spolski
19 Sequential Roles of IL-6, IL-21, and IL-23 in T H 17 Lineage Differentiation +IL-21 Ag TCR IL-6R IL-12Rβ1 Stat3 Il21 R IL-21R IL-6R IL-23R Stat3 Il23r IL-21R Stat3 IL-23 Il17 IL-21R IL-23R IL-6R Stat3 IL-23R R Il17 IL-21R IL-6 IL-21 +IL-23 Stat3 Il17 T H 17 lineage commitment
20 Summary IL-6 induces expression of IL-21 that amplifies an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4+ T cells. Both IL-21 and IL-23, along with, induce IL-17 expression independently of IL-6. IL-21 and IL-23 induce the orphan nuclear receptor, which in synergy with STAT3 promotes IL-17 expression.
21 How does function in induction of both anti-inflammatory Foxp3 + Treg cells and proinflammatory T H 17 cells?
22 inhibits -induced expression of IL-17 None (added Day 0) (added Day 1) 0.1 MIG MIG MIG IL GFP L. Zhou
23 Foxp3 Exon 2 Repressor domain Zinc finger Leucine Zipper Forkhead DNA-binding Domain Forkhead/winged-helix transcription factor Necessary for development and sufficient for some of the functions of Treg cells Mutated in human IPEX Patients Alternate splice isoform (ΔEx2) in humans retains repressor function
24 -WT ΔEx2 WT ΔEx2 Association of Foxp3 with Depends in Part On Alternately Spliced Product of FOXP3 Exon 2 FLAG Flag IP α-flag α-rorγ Total lysate α-flag α-rorγ Human Mouse J. Lopes, S. Ziegler M. Chong, L. Zhou
25 Foxp3Δex2 Has Reduced Activity in Repressing IL-17 Induction
26 Inhibition of TGFβ-induced by Foxp3 R Smads Foxp3? IL-17
27 Does induce T cells with dual differentiation potential? Naive IL-6 / IL-17 Foxp3 IL-21 IL-23 / IL-17 Foxp3
28 + Foxp3 + Cells Exist in Vivo Rorc(γt) gfp/+ CD4 + GFP int CD4 + GFP Foxp CD CD4 Small Intestinal Lamina Propria T Cells
29 Inhibits IL-23R Expression in a Dose-Dependent Manner 250 IL-23R mrna IL IL IL
30 IL-23R Signaling Down-Regulates Level of -Induced Foxp3 No cytokine IL MIG Foxp IL-23R GFP
31 IFNγ IL-4 T h 17 IL-25 IL-27 IL-6 IL-21 SOCS3 STAT3 STAT5 IL-2 IL-23 IRF4 Foxp3 RA TCR Foxp3 IL-17
32 Dendritic Cells Dendritic Cells RA IL-2 Foxp3 Foxp3 Foxp3 Th17 Dendritic Cells Dendritic Cells itreg itreg Foxp3 Foxp3 Foxp3 Foxp3 Foxp3 Foxp3 Metastable Dendritic Cells Dendritic Cells Foxp3 Foxp3 itreg Foxp3 Th17 IL-6 IL-21 IL-23 Th17
33 Lumen Commensal flora Pathogens M CD103+ ILFs RA IL-10 IL-23 IL-6 CD11b + CD103 - Cryptopatches Treg Treg Treg Treg Treg? Th17 Th17 Th17? Lamina Propria
34 Implications of Foxp3: Interaction balance of full length versus Δexon2 FOXP3 may determine frequency of T H 17 cells mutations in FOXP3 or in -responsive regulatory sequences would favor differentiation of more T H 17 cells polymorphism in IL-23R that favors protection from Crohn s disease may affect Foxp3: balance
35 Benaroya Institute Jared Lopes Steve Ziegler NIH/NHLBI Rosanne Spolski Warren Leonard NYU School of Medicine Liang Zhou Ivo Ivanov Mark Chong Roy Min Alice Lepellay Kevin Shenderov Gabriel Victora Carlos Tadokoro Juan Lafaille David Levy Univ. Mainz Markus Neurath Moritz Leppkes Christoph Becker DNAX Brent McKenzie Dan Cua
36 STAT3 STAT3 IL-23 IL-6 + STAT3 IL-21 STAT3 IL-23R + + STAT3 IL-17
37 Experimental System Naïve CD4+ T cells cytokines retrovirus YYYYYYYYYYYYYYYY /IL-23R GFP/Thy1.1 LTR IRES LTR Realtime PCR analysis Cytokine intracelluar staining hours 96 hours
38 IL-21 Signaling Induces, IL-17 and IL-17F IL-17F None 0.2 IL-21+ IL Rorγt +/ IL-17 Rorγt gfp/gfp IL-6 IL * HMG1
39 Model of Th17 Development IL-6 Ag IL-12Rβ1 TCR IL-6R Stat3 Il21 R IL-21R IL-6R + IL-21 IL-23R Stat3 Il23r IL-21R Stat3 IL-23 Il17 IL-21R IL-23R IL-6R Stat3 IL-23R R Il17 IL-21R IL-6 IL-21 + IL-23 Stat3 TCR IL-6R Ag + IL-12Rβ1 Foxp3 IL-6 /IL-21 /IL-23 R Foxp3 itreg Foxp3 Il17 T H -17 lineage commitment
40 Cytokine Contributions in Th17 Cell Differentiation IL-23, a member of IL-12 cytokine family, contains the common p40 chain and a unique p19 chain IL-23 signals through a heterodimeric receptor complex consisting IL-12Rβ1 and IL-23R IL-23 (p19) ko mice are protected from autoimmune diseases (EAE, IBD, etc.) due to lack of Th17 cells, but have normal Th1 responses IL-23 cannot drive naïve T cells into the Th17 lineage IL-6 and, a well known anti-inflammatory cytokine, are required for differentiation of inflammatory Th17 cells
41 IL-23 Enhancement of Th17 Cell Differentiation at Low Concentrations of 25 IL-17 + Cells (%) IL-6 IL-6 + IL-23 0 (ng/ml)
42 DC-derived Retinoic Acid promotes Treg and inhibits Th17 cell differentiation + Th17 cell X Cheroutre Powrie Noelle Belkaid
43 IL-23R IL-23R IL-23R
SUPPLEMENTARY INFORMATION
doi: 1.138/nature89 IFN- (ng ml ) 5 4 3 1 Splenocytes NS IFN- (ng ml ) 6 4 Lymph node cells NS Nfkbiz / Nfkbiz / Nfkbiz / Nfkbiz / IL- (ng ml ) 3 1 Splenocytes IL- (ng ml ) 1 8 6 4 *** ** Lymph node cells
Supplemental Figure 1. Signature gene expression in in vitro differentiated Th0, Th1, Th2, Th17 and Treg cells. (A) Naïve CD4 + T cells were cultured
Supplemental Figure 1. Signature gene expression in in vitro differentiated Th0, Th1, Th2, Th17 and Treg cells. (A) Naïve CD4 + T cells were cultured under Th0, Th1, Th2, Th17, and Treg conditions. mrna
SUPPLEMENTARY INFORMATION
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