5/21/2014 Innate cell derived cytokines as determinants of effector T cell fate decisions during autoimmune inflammation of the CNS Thomas Korn Technische Universität München CMSC/ACTRIMS cooperative annual meeting Dallas, TX, May‐30, 2014 Multiple sclerosis ‐ Basic science session 1. Identify key concepts of the immunologic and neuropathologic disease processes associated with multiple sclerosis (MS). 2. Recognize that the pathophysiology of MS is affected by gender, ethnocultural origin, and environmental factors and tailor diagnosis and management appropriately. Concept: Re‐programming of pathogenic T helper cells in CNS autoimmunity 1 5/21/2014 Active MS lesion Histology CD4 CD3 CD22 Windhagen et al. 1995, JEM Effector T helper cell subsets in CNS autoimmunity IL‐12 STAT4 T-bet Th1 (IFN-) IL‐23 STAT3 RORt Th17 (IL-17, IL-17F, IL-21, IL-22) Naïve T cell Epithelial surfaces (Skin, gut, lungs) Maybe CNS? 2 5/21/2014 Experimental Neuroimmunology Dendritic cells orchestrating the T cell response … … by shaping T cell phenotypes in the periphery: Source: Nature reviews immunology ‐ Dendritic cells poster, Miriam Merad, 2011 Experimental Neuroimmunology Dendritic cells orchestrating the T cell response … … by local antigen presentation and T cell modulation in the CNS: Source: Edited from Miller et al., 2007 (NRI) & Zozulya et al. , 2008 (NCP) 6 3 5/21/2014 Experimental Neuroimmunology Dendritic cells orchestrating the T cell response … … by local antigen presentation and T cell modulation in the CNS: Source: Edited from Miller et al., 2007 (NRI) & Zozulya et al. , 2008 (NCP) 7 IL‐23 deficient mice are resistant to autoimmunity Oppmann et al. 2000 (Immunity, 13:715) Cua et al. 2003 (Nature, 421:744) No EAE No CIA No EAU But still systemic inflammatory response 4 5/21/2014 IL‐10 and IFN‐γ production by CD4+ T cells are required for the resolution of CNS inflammation Il23r+/Il23r-/Il23r-/- x Il10-/Il23r-/- x Il10-/- x Ifng-/- EAE Score 4.0 3.0 2.0 1.0 0.0 0 5 10 15 20 25 Days after immunization Heinemann et al. 2014, Nature Communications [In Press] Effector T cells in the CNS of TKO mice Il23r+/‐ KO TKO 5 5/21/2014 The IL‐12 family of cytokines Hunter 2005, Nat. Rev. Immunol. Differentiation of Tr‐1 cells CD4+ TGF‐ + IL‐27 GFP‐ Tr‐1 IFN‐ Starting population: CD4+CD62LhighFoxp3‐ APC free system IL‐10 Awasthi et al. 2007, Nature Immunology Fitzgeral et al. 2007, Nature Immunology 6 5/21/2014 Which transcription factors are different ? Tr‐1 TC naïve TH17 Blimp1 is expressed in Tr‐1 but not in Th17 cells Heinemann et al. 2014, Nature Communications [In Press] 7 5/21/2014 Blimp1 dependent IL‐10 secretion in CD4+ T cells IL-10 IL-10 Blimp1 Blimp1 in B cells: B lymphocyte‐induced maturation protein 1 (gene: Prdm1) Plasma cell maturation Antagonist of Bcl6 Blimp1 in T cells: Effects on quantity of effector CD8+ T cell population Upregulation of IL‐10 in CD8+ effector T cells Blimp1 (together with IRF4) is required for IL‐10 production in Foxp3+ Tregs 8 5/21/2014 Re‐programming of Th17 cells IL‐12R and IL‐23R on committed T cell subsets 100 100 Il23r 1000 10 10 7) (T -6 IL -1 2 + + an ti- IL IL -4 (T na T -6 IL + T h1 iv h1 e 7) (T (T -4 IL h1 h1 e iv na T tian + 2 -1 IL ) 1 ) 1 T Il12rb2 1000 9 5/21/2014 IL‐12 and IL‐27 (but not IL‐23) induce Blimp1 in pre‐committed Th17 cells Blimp1 Actin Heinemann et al. 2014, Nature Communications [In Press] IL‐12 and IL‐27 (but not IL‐23) induce IL‐10 and IFN‐g in pre‐committed Th17 cells Th17.R2 10 5/21/2014 Re‐programming of Th17 cells by IL‐27 IL-27 IL-27R (pStat1), pStat3 Blimp1 Il10 IL-10 See also: Stumhofer et al. 2007, Nat. Immunol.: Induction of IL‐10 in Th1 cells by IL‐27 in a Stat1 and Stat3 dependent manner IL‐12 induces phosphorylation of Stat4 in Th17 cells 11 5/21/2014 pStat4 binds to the Blimp1 locus Heinemann et al. 2014, Nature Communications [In Press] IL‐12 induces Blimp1 in IL‐17+ Th17 cells R2 IL-12 IL-23 Blimp1 Actin 12 5/21/2014 Re‐programming of Th17 cells by IL‐12 Th17 IL-12 IL-12R pStat4 Blimp1 Il10 IL-10 Th17 IL-17 IFN-γ What about in vivo? 13 5/21/2014 Blimp1 CKO mice develop severe EAE Standard EAE protocol: 200µg MOG35‐55/CFA plus 200ng PTX Suboptimum EAE protocol: 200µg MOG35‐55/CFA plus 50ng PTX Blimp1 CKO mice show reduced numbers of IL-10+ T cells in the CNS 14 5/21/2014 Blimp1 deficiency in T cells rescues the phenotype of Il23r disruption Heinemann et al. 2014, Nature Communications [In Press] Summary Th17 cells respond to both IL‐12 and IL‐27 (in addition to IL‐23) IL‐27 is a strong inducer of IL‐10 in pre‐committed Th17 cells IL‐27 (and also IL‐12 via Stat4) drive Blimp1 expression in Th17 cells and induce IL‐10 and IFN‐γ The production of IL‐10 and IFN‐γ in CD4+ effector T cells is a non‐redundant T cell intrinsic means to restrain inflammation and immunopathology during CNS autoimmunity. 15 5/21/2014 Perpetuation of inflammation Resolution of inflammation Fates of CD4+ T cells in the peripheral immune compartment IL‐12 Naïve T cell STAT6 GATA3 c‐maf IL‐4 IL‐23 Foxp3 STAT4 T‐bet c‐Maf Ahr STAT3 RORt Th1 (IFN‐): Host defense (IC pathogens) Autoimmunity Th2 (IL‐4, IL‐5, IL‐13, IL‐25): Host defense (parasites) Allergy, asthma Th17 (IL‐17, IL‐17F, IL‐21, IL‐22): Host defense (EC pathogens) Inflammation, autoimmunity Tr‐1 (IL‐10, IFN‐): Downregulation of immunopathology T‐reg (TGF‐, IL‐10): Tolerance, immunosuppression 16 5/21/2014 CD4+ T cell population isolated from the CNS at the peak of EAE CD3+CD4+ gate IL‐17 IL‐10 CD3+CD4+Foxp3‐ gate IFN‐γ Foxp3 (GFP) Feedforward regulation during ongoing inflammation (released only in the absence of IL‐23) IL‐10 T effector cell Treg Chaudhry et al. 2011 (Immunity) 17 5/21/2014 Disease activity Regulation of CNS inflammation SPMS CDMS CIS Threshold of clinical manifestation Time Nature Genetics (2013), 45.1353 18 5/21/2014 Ustekinumab (anti‐p40) has a “zero” net effect in MS Segal et al. 2008, Lancet Neurology Acknowledgment Technische Universität München Sylvia Heink Christian Peter Franziska Petermann Christina Heinemann Christopher Sie Anna‐Lena Vogel Meike Mitsdoerffer Veit Rothhammer WEHI, Melbourne Axel Kallies Klinik und Poliklinik für Neurologie des Klinikums rechts der Isar, TUM Bernhard Hemmer Seattle Children’s Hospital Mohamed Oukka KKF [email protected] SFB 1054 19 5/21/2014 Thank you for your attention 20
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