Tissue-resident innate immunity in the lung

Abstract

The lung is a unique organ that must protect against inhaled pathogens and toxins, without mounting a disproportionate response against harmless particulate matter and without compromising its vital function. Tissue-resident immune cells within the lung provide local immunity and protection from infection but are also responsible for causing disease when dysregulated. There is a growing appreciation of the importance of tissue-resident memory T cells to lung immunity, but non-recirculating, tissue-resident, innate immune cells also exist. These cells provide the first line of defence against pulmonary infection and are essential for co-ordinating the subsequent adaptive response. In this review, we discuss the main lung-resident innate immune subsets and their functions in common pulmonary diseases, such as influenza, bacterial pneumonia, asthma and inflammatory disorders.

Keywords: innate; lung; tissue-resident.

Figure 1

Tissue‐resident macrophages persist within lung tissues where they provide protection from inhaled pathogens and allergens but simultaneously prevent overt responses to harmless particulate matter. Interstitial macrophages (IM), which populate the lung interstitium, primarily derive from recruited blood monocytes, although a portion may be resident. At least two distinct subsets can be described, with respective roles in homeostasis or antigen presentation. IMs produce immunoregulatory cytokines both at steady state, and after exposure to environmental stimuli, which allows them to modulate inflammation. Alveolar macrophages (AM) are a self‐renewing population of resident macrophages within the alveolar space that do not rely on replenishment from the bone marrow. Primarily anti‐inflammatory cells, they mediate inflammation and promote homeostasis through phagocytosis of apoptotic cells before lysis and the production of anti‐inflammatory cytokines such as transforming growth factor‐β. AMs also provide protection from inhaled pathogens through phagocytosis and the recruitment of inflammatory cells which clear infections.

Figure 2

Innate lymphoid cells (ILCs) and natural killer (NK) cells are important tissue‐resident cells and mediators of homeostasis within the lung. NK cells are recruited during infection, although potentially resident populations have been described. NK cells are cytolytic cells that produce granzymes that mediate killing of infected macrophages. NK cells themselves are susceptible to direct infection by influenza but remain important producers of interferon‐γ (IFN‐γ), which contributes to inflammation. ILC1s are non‐cytotoxic counterparts of NK cells. That produce IFN‐γ and are important mediators of inflammation and viral clearance. Dendritic cell (DC) ‐derived interleukin‐12 (IL‐12) and IL‐18 can transition ILC2s into ‘ILC1‐like’ cells which may play a pathological role in chronic obstructive pulmonary disease. ILC2s produce type 2 cytokines IL‐5 and IL‐13, which are important in allergic responses and helminth clearance in the lung. They also facilitate tissue repair through their production of amphiregulin. ILC3s are the most abundant ILC subset in the human lung. IL‐22 producing ILC3s are important for bacterial clearance and tissue repair, while IL‐17 from ILC3s contributes to inflammation but may also have an important role in protection from extracellular bacteria and fungi.

Figure 3

Dendritic cells (DCs) are professional antigen‐presenting cells that sample and present antigen to T cells within the lamina propria and associated lymph nodes. Although lung DCs may not be tissue‐resident in the strictest sense (because they do not appear to self‐renew), they can arise from precursor cells and persist in the lung for up to 8 weeks. DCs of the lung are heterogeneous and different subsets have different immunogenic functions. Epithelial DCs express CD103 and sample antigen from the alveolar space. These cells limit allergic inflammation through interleukin‐12 (IL‐12) and prevent fatal inflammatory responses via IL‐2. CD11b⁺ DCs traffic antigen to the lymph node where they coordinate T helper type 2 responses to house dust mite challenge. In cancer, the balance between CD103⁺ DCs and CD11b⁺ DCs is important and is being exploited in novel treatment strategies.