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Dale T. Umetsu , MD, PhD The Prince Turki al Saud Professor of Pediatrics

Innate Lymphoid Cells, Viral Infection and the Development of Asthma. Dale T. Umetsu , MD, PhD The Prince Turki al Saud Professor of Pediatrics Harvard Medical School Division of Immunology and Allergy Children ’ s Hospital Boston dale.umetsu@childrens.harvard.edu.

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Dale T. Umetsu , MD, PhD The Prince Turki al Saud Professor of Pediatrics

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  1. Innate Lymphoid Cells, Viral Infection and the Development of Asthma Dale T. Umetsu, MD, PhD The Prince Turki al Saud Professor of Pediatrics Harvard Medical School Division of Immunology and Allergy Children’s Hospital Boston dale.umetsu@childrens.harvard.edu

  2. Asthma, an inflammatory disease of the airways Mast cell Nature Reviews Immunology

  3. Many observations in human asthma cannot be explained by the Th2 paradigm • The prevalence of asthma has increased dramatically over the past 30 years, despite a major increase in the use of corticosteroids. • IFN-, IL-17 and neutrophils are frequently found in the lungs. • Many non-Th2 factors such as viruses, air pollution and exercise, cause asthma. • Most patients who are sensitized to allergens do not develop asthma. • Th2 targeted treatments have not been as effective as hoped in many clinical studies of asthma.

  4. Asthma is a Heterogeneous and Complex Trait, with at Least Several Distinct Phenotypes Eosinophils, adaptive immunity Neutrophils, innate immunity Kim et al. Nature Immunol. 2010. 11:557 Other factors and components of immunity, in addition to Th2 cells, must regulate and shape the development of asthma.

  5. Mouse Models of Asthma ≠ • Mice are not humans. • So what we find in mice is not always applicable. • However, many of the foundations of immunology were first established in mice. • Th1, Th2, Th17, Treg cells, DC, TLRs. • Mouse models of asthma can be used to dissect the many of these different pathways that lead to asthma. • Mice develop AHR and airway inflammation.

  6. BALB/c OVA BALB/c PBS CD1d KO OVA J a KO OVA 6 4 RL (cm H20 / ml / sec) 2 Methacholine (mg/ml) Kim et al, 2008. Nature Medicine. 14:633. Many Paths to Asthma: Mouse Models 0 2.5 5 7.5 10 Akbari et al, 2003. Nature Medicine. 9:582. Pichavant et al, 2008. J Exp Med. 208:385. Ozone Viral infection Allergen

  7. Different Models of Asthma, with Distinct Requirements Asthma Model Requirement NKT cells for Th2 cells required Allergic asthma yes yes Ozone/Air pollution no yes Sendai virus asthma no yes

  8. A Role for NKT cells in Asthma • NKT cells comprise a subset of T cells that rapidly produce cytokines. • Most NKT cells express a semi-invariant TCR: V14-J18 (mice) or V24-J18 (humans). • This invariant TCR is highly conserved across many species, suggests that this iTCRis a Pattern Recognition Receptor. • NKT cells respond to glyoclipid antigens, expressed by some allergens, bacteria and possibly fungi.

  9. Another Mouse Model of Asthma • Another mouse model of asthma that can help to further understand and explain the heterogeneity in asthma. • Involves a non-allergic form of asthma and innate immunity.

  10. An Asthma Phenotype Caused by Viral Infection • Acute viral respiratory infections profoundly affect asthma. • In individuals with established asthma, most respiratory viral infections, trigger acute symptoms of asthma. • H1N1 pandemic influenza A infection caused particularly severe disease in patients with asthma. • The specific pathological pathways triggered by influenza that result in asthma are not fully understood.

  11. Influenza might activate innate pathways that affect asthma, independent of Th2 cells. • We examined the effects of influenza A virus: • By infecting mice, and examining the mechanisms that directly lead to AHR.

  12. H3N1 infection in adult mice Methacholine (mg/ml)

  13. The influenza induced AHR response is not strain dependent Penh

  14. H3N1 Causes Airway Inflammation

  15. IL-13 is required for H3N1-induced AHR Methacholine (mg/ml)

  16. H3N1 infection in adult RAG-/- mice Methacholine (mg/ml) H3N1-induced AHR developed through innate immune pathways that did not require T cells, B cells, or even NKT cells. Chang YJ, et al. 2011. Nature Immunol.

  17. CD1d-/- mice develop H3N1 induced AHR Methacholine (mg/ml)

  18. IL-33 induces AHR in Rag2-/- mice Kim et al. 2012. JACI

  19. What is IL-33? • Member of the IL-1 cytokine family. • Found in the lungs of patients with severe asthma, and in the blood during anaphylaxis. • Produced by epithelial cells and macrophages. • Binds to its receptor, ST2, expressed on mast cells, basophils, eosinophils and Th2 cells. • IL33 and ST2 are important asthma susceptibility genes, as shown by GWAS. • Treatment of mice with IL-33 induces AHR and the production of Th2 cytokines (IL-13 and IL-5), even in the absence of T cells or B cells.

  20. Alveolar Mac IL-33 mRNA IL-33+ cells (x104) IL-33 production increases in the lungs of H3N1 infected mice

  21. H3N1-induced AHR requires ST2, the IL-33R H3N1 infection Allergen An IL-33 / ST2 axis was required for H3N1-induced AHR, but not for OVA-induced AHR. Chang YJ, et al. 2011. Nature Immunol.

  22. What cells respond to IL-33? • Cell types that express ST2 and respond to IL-33: • Th2 cells, eosinophils, mast cells, NKT cells. • Nuocytes(A McKenzie), natural helper cells (S Koyasu), Ih2 cells (R Locksley), or multipotent progenitor cells (D Artis). • Lin-, cKit+, ST2+, IL-25 receptor+ and Sca1+. • Have features of stem cells (CD34+cKit+). • Produce large amounts of IL-13 and IL-5. • Identified in the intestines during helminth infection. • Nuocytes/natural helper cells belong to a family of evolutionarily conserved effector cells, called innate lymphoid cells.

  23. Innate Lymphoid Cells Innate immunity (ILC) Adaptive immunity (CD4 T cells) NK cells, ILC1 IFN-g Th1 cells (T-bet) Nuocytes, ILC2 (RORa) IL-13, IL-5 Th2 cells (Gata3) ILC17 cells (RORgt) Th17 cells (RORgt) IL-17 Th22 cells (RORgt) IL-22 NK22 cells (RORgt) LTi cells (RORgt) TReg cells (Foxp3)

  24. IL-17 and IL-22 • IL-17 • Made by Th17 cells, ILC17 cells, NKT cells and gd T cells. • Key roll in autoimmune disease. • Colitis, multiple sclerosis, diabetes, RA, psoriasis. • Induced with TGF- and IL-6, IL-23 or IL-1b. • Important for protection against fungi. • AIRE deficiency patients have anti-IL-17 antibody; Stat3 mutations reduced Th17 cell development. • IL-22 • IL-10 family member. • Made by Th22 cells, ILC22 cells and DCs. • Enhances epithelial cell and hepatocyte survival. • Induces defensin production from epithelial cells.

  25. Innate Lymphoid Cells ROR IL-7 Asthma IL-13, IL-5 Id2 NK22 ILC22 Spits et al. Nature Immunol. 2011. 12:21

  26. Nuocytes are present in the lungs ST2 Chang YJ, et al. 2011. Nature Immunol.

  27. Number of CD45+Lin-ST2+cKit+Sca1+ nuocytes in the lung The number of nuocytes in the lung peaks on day 6 of infection.

  28. The major IL-13 producing cells in the lungs are nuocytes

  29. Nuocytes are producing IL-5 Nuocytes produce IL-5 during influenza infection, but eosinophil recruitment to the lungs is blocked by the presence of high levels of IFN-g.

  30. IL13-/- recipients IL13+/+ nuocytes (H3N1) IL13+/+ nuocytes (mock) IL13-/- nuocytes (H3N1) IL13-/- nuocytes (mock) Deletion of nuocytes abolishes H3N1 induced AHR andAdoptive transfer of nuocytes restores H3N1 induced AHR Deletion in Rag2-/- mice Adoptive transfer into IL-13-/- mice IL-13 producing nuocytes play a major role in mediating H3N1-induced AHR. Chang YJ, et al. 2011. Nature Immunol.

  31. Are Nuocytes Required for the Clearance of Influenza Infection? Nuocytesplay a minor role in clearing influenza infection.

  32. Influenza A AM IM Epithelial cells DC ? IL-33 Y Y ST2 Nuocytes/NH cells IL-13, IL-5 Acute asthma Mucus secretion Smooth muscle contraction

  33. Nuocytes in Asthma • In a protease allergen model of airway inflammation, nuocytes are a critical source of Th2 cytokines (Halim et al. 2012. Immunity). • Nuocytes are a source of amphiregulin, which restores airway epithelial integrity after influenza infection (Monticelli et al. 2011. Nature Immunol). • Nuocytes infiltrate the lungs during allergen challenge (Barlow et al. 2011. JACI). • Nuocytes interact with iNKT cells and alveolar macrophages to induce AHR (Kim et al. 2012. JACI).

  34. Protease Allergens Induce IL-33 Production Halim et al. 2012. Immunity

  35. Activation of NKT cells induces AHR and requires IL-33 (Kim et al. 2012. JACI)

  36. Kim et al. 2012. JACI

  37. Are Nuocytes Important in Human Asthma? Allakhverdi. et al. 2009. JACI. 123:472. Also present in human nasal polyp tissue, but not in non-inflamed nose tissue. (Mjosberg et al. 2011. Nature Immunol. 12:1055)

  38. Summary • Asthma is a very heterogeneous inflammatory disease of the airways. • Mouse models have helped to sort out the heterogeneity. • Infection with H3N1 influenza A virus resulted in severe AHR. • Occurred in the total absence of adaptive immunity. • Influenza virus activated alveolar macrophages, resulting in the production of IL-33. • IL-33 activated nuocytes, which produced large quantities of IL-13 and were required for AHR. • Targeting innate lymphoid cells may provide new and effective therapies for some forms of asthma.

  39. Allergic and NonAllergic Pathways in Asthma Th2 cell B cell NKT cell DC Allergen, endotoxin, injury Nuocyte IL-4 IL-5 IL-13 IL-25 IL-33 TSLP Allergic Asthma Steroid responsive Mast cell Epithelial cells Eosinophil Basophil Interaction? Injury, ozone, viral, bacterial infection Th17 cell NKT cell Innate lymphoid cell DC Epithelial cells IL-12 IL-18 IL-1 IL-33 IL-17 IFN- Other? Non-allergic Asthma Steroid unresponsive  T cell Macrophage, or alternatively activated macs neutrophil

  40. Acknowledgements Ya Jen Chang Hye Young Kim Lee Albacker Hyun Hee Lee Ya-Ting Chuang Gwangwu Chen Rosemarie DeKruyff Sheena Monahan Philippe Stock, now at Charite Hospital, Berlin Omid Akbari, now at Univ Southern California Muriel Pichivant, now at Pasteur Institute Nicole Baumgarth, Univ Calfornia, Davis Petr Ilarionov, University of Birmingham, UK Gurdyal Besra, University of Birmingham, UK Michio Shimamura, Mitsubishi Kagaku Institute Paul B. Savage, Brigham Young University Dirk Zajonc, La Jolla Institute for Allergy and Immunology John Faul, Connelly Hospital, Dublin, Ireland Stephanie Shore, Harvard School of Public Health Takashi Yamamura, National C of Neuro Peter van den Elzen, U Britch Columbia Ben Appelmelk, Vrje Univ Med Center Richard Franck, Hunter College, NY Andrew McKenzie, MRC, UK Dirk Smith, Amgen Mark Exley, Harvard Medical School Masaru Taniguchi, RIKEN Institute Toshinori Nakayama, Chiba University Richard Blumberg, Brigham and Women’s Michael Grusby, Harvard School of Public Health Shizuo Akira, Osaka University Y. Iwakura, University of Tokyo Elliot Israel, Brigham and Women’s NIH Tetramer Facility

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