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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

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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


Asthma, an inflammatory disease of the airways

Mast cell

Nature Reviews Immunology

many observations in human asthma cannot be explained by the th2 paradigm
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.
asthma is a heterogeneous and complex trait with at least several distinct phenotypes
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.

mouse models of asthma
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.
many paths to asthma mouse models









RL (cm H20 / ml / sec)


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.


Viral infection


different models of asthma with distinct requirements
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

a role for nkt cells in asthma
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.
another mouse model of asthma
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.
an asthma phenotype caused by viral infection
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.
influenza might activate innate pathways that affect asthma independent of th2 cells
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.
h3n1 infection in adult mice
H3N1 infection in adult mice

Methacholine (mg/ml)

h3n1 infection in adult rag mice
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.

what is il 33
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.
h3n1 induced ahr requires st2 the il 33r
H3N1-induced AHR requires ST2, the IL-33R

H3N1 infection


An IL-33 / ST2 axis was required for H3N1-induced AHR, but not for OVA-induced AHR.

Chang YJ, et al. 2011. Nature Immunol.

what cells respond to il 33
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.
innate lymphoid cells
Innate Lymphoid Cells

Innate immunity (ILC)

Adaptive immunity (CD4 T cells)

NK cells, ILC1


Th1 cells (T-bet)

Nuocytes, ILC2 (RORa)

IL-13, IL-5

Th2 cells (Gata3)

ILC17 cells (RORgt)

Th17 cells (RORgt)


Th22 cells (RORgt)


NK22 cells (RORgt)

LTi cells (RORgt)

TReg cells (Foxp3)

il 17 and il 22
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.

Innate Lymphoid Cells




IL-13, IL-5




Spits et al. Nature Immunol. 2011. 12:21

nuocytes are present in the lungs
Nuocytes are present in the lungs


Chang YJ, et al. 2011. Nature Immunol.

number of cd45 lin st2 ckit sca1 nuocytes in the lung
Number of CD45+Lin-ST2+cKit+Sca1+ nuocytes in the lung

The number of nuocytes in the lung peaks on day 6 of infection.

nuocytes are producing il 5
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.


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.

are nuocytes required for the clearance of influenza infection
Are Nuocytes Required for the Clearance of Influenza Infection?

Nuocytesplay a minor role in clearing influenza infection.


Influenza A



Epithelial cells







Nuocytes/NH cells

IL-13, IL-5

Acute asthma

Mucus secretion

Smooth muscle contraction

nuocytes in asthma
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).

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)

  • 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.
allergic and nonallergic pathways in asthma
Allergic and NonAllergic Pathways in Asthma

Th2 cell B cell NKT cell


Allergen, endotoxin, injury








Allergic Asthma

Steroid responsive

Mast cell

Epithelial cells




Injury, ozone, viral, bacterial infection

Th17 cell NKT cell Innate lymphoid cell


Epithelial cells








Non-allergic Asthma

Steroid unresponsive

 T cell

Macrophage, or alternatively activated macs




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