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Cambridge Immunology Network

The plasticity of innate lymphoid cells

Dr Hergen Spits talks about innate lymphoid cells and their role in chronic inflammatory diseases


Innate lymphoid cells (ILCs) are part of the innate immune system and have recently risen to prominence due to their functional heterogeneity and role in several disease states involving chronic inflammation, such as Crohn’s disease, chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis (CRS). Dr Hergen Spits, Professor of Immunology at the Academic Medical Center (AMC) in Amsterdam, recently talked about his work on the plasticity of ILCs and their response to immune cells1 at the Cambridge Immunology Network.

Classification

ILCs have a lymphoid morphology but are non-T, non-B, non-myeloid cells. They are distributed throughout lymphoid and non-lymphoid tissues and can be defined by the expression of key cell surface markers (CD127+/-, CD161, and CRTH2). ILC functional diversity is similar to T cells and they can be grouped into cytotoxic and non-cytotoxic cells (the latter are further divided into three classes: ILC1, ILC2 and ILC3):

  • Cytotoxic ILCs (CD94+)
    • NK cells: provide immunity against viruses and cancer, and are involved in chronic inflammation.
  • Non cytotoxic ILCs
    • T-bet+ ILC1s: provide immunity against intracellular bacteria and protozoa, and are involved in chronic inflammation.
      • CD127-
      • CD127+CD161+
    • GATA3+ ILC2s: provide immunity against parasitic worms (helminths), and are involved in asthma, the allergic response, and metabolic homeostasis.
      • CD127+CD161+CRTH2+
    • RORγt+ ILC3s: provide immunity to extracellular bacteria, and are involved in lymphoid tissue development, intestinal homeostasis and chronic inflammation. Subdivided further into two classes:
      • Lymphoid tissue inducer (LTi) cells CCR6+T-bet-
        • c-kit+NKp44+BDCA4+ (neuropilin 1)
        • CCR6-T-bet+
          • c-kit+NKp44+

ILCs and Crohn’s disease

In the normal non-inflamed gut,  ILC3s that secrete IL-22 are predominant and are thought to be protective against colitis and confer wound healing, in part by dampening the activation of  Th17 cells. In Crohn’s disease, levels of ILC3s decrease whilst ILC1 levels increase through the action of IL-2 and IL-12.

Dr Spits and his lab showed that the protective RORγt+NKp44+ ILC3s secrete anti-microbial peptides. These ILC3s then transdifferentiate into ILC1s that secrete IFNγ to induce a chronic inflammatory state. This was demonstrated by culturing fetal gut NKp44+ ILC3s with IL-2 and IL-12, which caused them to rapidly lose expression of NKp44 and c-kit and acquire the ILC1 phenotype2. CD14+ dendritic cells are likely to be an additional source of the IL-2 and IL-12 cytokines, as well as secreting IL-22 binding protein (BP), which counteracts the effects of IL-22.

ILCs and chronic obstructive pulmonary disease

In  COPD, the lung is chronically inflamed and ILC1s are present at higher levels than normal, while ILC2 and ILC3 levels are reduced. Dr Spit’s hypothesis was that ILC2s that were normally in the lung, transdifferentiate to ILC1s due to the presence of of IL-1β  and IL-12 in the lung.

Single cell cloning of ILC2s purified from peripheral blood in the presence of IL-1β and IL-12 showed heterogeneity upon analysis, indicating a phenotypic change. The transdifferentiated ILC1s can then secrete IFNγ to produce chronic inflammation of the lung seen in COPD.

Interestingly, research showed that ILCs are tissue-resident cells, whose pre-cursors are thought to reside in the tissue to replenish supplies, unlike T cells that are replenished from the circulation3. ILCs can therefore be thought of as ‘sedentary’ cells, watching over and maintaining local tissue function.

ILCs and chronic rhinosinusitis

CRS is characterized by local type II-mediated inflammation with associated high levels of IL-4, IL-13, IgE, and eosinophil infiltration. However, Th2 cells alone do not account for the high levels of IL-4 and IL-13, suggesting the potential involvement of ILC2s.

ILC2s are present at higher levels in CRS tissues, and may be maintained by IL-4 that has been secreted by activated eosinophils. This in turn stimulates ILC2s to secrete IL-5, a growth factor for eosinophils, creating a positive feedback loop. Immunohistochemistry of the nasal polyps in CRS patients showed co-localization of eosinophils and ILC2s, implicating both eosinophils and ILC2s in CRS.

The receptor CRTH2, a key marker for ILC2 cells, has been shown to play a key role here. By targeting prostaglandin D2 (PGD2), a ligand of CRTH2, using monoclonal antibodies or small molecule antagonists (eg TM30089), ILC2 migration can be inhibited along with PGD2 induced cytokine production. Inhibiting ILC2 migration inhibition by targeting PGD2 could have therapeutic benefits for CRS patients.

Cell-cell effects?

At the end of the talk, Dr Spits answered an interesting question from the audience regarding the possibility that the transdifferentiation of the ILCs might be a result of cell-cell interactions in addition to the effects of secreted cytokines. Dr Spits acknowledged that this might be a possibility and it is a topic that warrants further investigation.

References

1.   Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

2.   Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–9 (2013).

3.   Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

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