Figure 3.

Proposed mechanisms by which unconventional lymphocytes promote lung repair. Damage can be induced by chemical exposure or infection with viruses or helminths, which leads to IL-33 release by damaged epithelium. This activates ILC2, stimulating the production of cytokines and Areg. Areg promotes epithelial cell proliferation, reepithelialisation, and goblet cell activity, strengthening the mucus barrier. The production of IL-13 and GM-CSF by ILC2 recruits macrophages and promotes their alternative activation, allowing them to contribute to repair. IL-13 also promotes epithelial cell differentiation and proliferation, and modulates collagen deposition. ILC2s also produce IL-5 which recruits eosinophils. These eosinophils can produce IL-4 and IL-13 and may therefore also contribute to healing. ILC2s may contribute to repair by upregulating Furin to promote the activation of MMPs and TGFβ, and they may directly regulate the extracellular matrix, but these mechanisms are yet to be proven. In neonatal lung γδ T cells respond to infection by producing IL-17 which stimulates IL-33 release by epithelial cells. Lung MAIT cells can become activated by TCR ligands from microbes, and cytokine signals from damaged cells, leading to the production of IFNγ, IL-17A/F and IL-22 which can promote epithelial proliferation. MAIT cells can also produce growth factors such as PDGF and VEGF which play a role in repair. Similar to ILC2s, MAIT cells can produce Areg which promotes epithelial cell turnover and goblet cell activity, and they may also upregulate furin to increase protein cleavage and activation. Created with BioRender.com.