LAUSR

Mucosalassociated invariant T (MAIT) cells are evolutionarily conserved innatelike T cells that play an important role in the maintenance of homeostasis of mucosal and nonmucosal barriers. They are highly abundant in the liver and blood and are also present in mucosal tissues. MAIT cells express a semiinvariant T cell receptor (TCR) recognising precursor derivatives of the riboflavin (vitamin B2) biosynthetic pathway, presented by the evolutionarily conserved, monomorphic major histocompatibility complex (MHC) class Irelated protein1 (MR1). Since these derivatives are strictly found in riboflavinsynthesising bacteria and yeasts, MAIT cells mediate a broad and potent antimicrobial reactivity. Activated MAIT cells rapidly secret proinflammatory cytokines, such as interleukin17 (IL17), interferon-γ (IFN-γ), and tumor necrosis factor (TNF) and exert cytolytic activity against cells presenting bacterial ligands on MR1. Additionally, MAIT cells can be activated in a TCR/MR1independent manner by several cytokines, including IL12, IL15, IL18 and type I interferons. 3 In this issue of Thorax, Kim and colleagues broaden our understanding of the pathological role of MAIT cells in acute respiratory distress syndrome (ARDS). ARDS is an acute respiratory illness featured by bilateral chest radiographical opacities with severe hypoxemia due to noncardiogenic pulmonary oedema. ARDS occurs most often in the setting of pneumonia, nonpulmonary sepsis, aspiration of gastric contents or severe trauma. The authors demonstrate that the frequency and the absolute number of circulating MAIT cells in patients with ARDS are significantly decreased compared with healthy controls (HCs) and correlates with the disease severity of ARDS. The majority of these patients (~70%) had pneumonia caused by bacteria and virus other than SARSCoV2. MAIT cells of ARDS patients are a potent IL17producing population with the capacity to concurrently produce IFN-γ (dualproducing) or IFN-γ and TNF (tripleproducing), similar to pathogenic Th17 cells. This study also revealed that IL17, TNF and IFN-γ secreted from activated MAIT cells of patients with ARDS potentiate macrophage activation to secrete cytokines including TNF, IL1β and IL8. Indeed, expression of the early activation marker CD69 and relatively to CD69, later activation marker programmed cell death protein 1 (PD1) were significantly higher on MAIT cells of patients with ARDS compared with that of HCs. The authors also underline that MAIT cells in bronchoalveolar lavage fluid (BALF) derived from patients with ARDS have higher expression of activation markers and production of IL17 than those in paired peripheral blood from the same patients with ARDS. Jouan and colleagues recently reported on phenotypical and functional alterations of unconventional T cells in patients with COVID19 presenting with ARDS. Among them, a significant decrease in the frequencies of circulating MAIT and invariant natural killer T (iNKT) cells was found in patients with severe COVID19. One possible explanation is recruitment of these cells from the blood into airways. The studies by Jouan and Kim clearly reveal that a decrease in circulating MAIT cells in patients with ARDS parallels their increase in airways, suggesting these cells contribute to the regulation of local inflammation. 6 Distinct immune populations such as innate lymphoid cells (ILCs) and unconventional T cells such as MAIT, γδT and iNKT cells play critical roles in lung homeostasis as well as being pathogenic mediators in lung disease due to the vulnerability of this organ to infection and injury. Emerging evidence indicates that MAIT cells are involved in TCRdependent and TCRindependent immune responses and possible immunopathogenesis in a variety of lung diseases. In agreement with previous reports, frequency of circulating MAIT cells in patients with COVID19 with acute lung inflammation is markedly reduced, and these cells exhibit an activated and cytotoxic phenotype that is more obvious in the lungs. In patients with asthma, disease severity is negatively correlated with the frequency of the MAIT cells in the blood, sputum and lung tissues, suggesting their protective effect against chronic inflammation. However, IL17producing MAIT cells are associated with the aggravation of symptoms in children with severe asthma. Patients with COPD also have a lower frequency of circulating CD8 and CD4CD8 MAIT cells, which is associated with disease severity. In patients with communityacquired pneumonia (CAP), MAIT cells in BALF actively produce IL17, which may be promoted by monocytederived inflammatory cytokines. IL17producing MAIT cells contribute to inflammation during CAP. Clearly, MAIT cells play opposite roles during microbial infections; a protective effect through secretion of IFN-γ and exacerbation of lung inflammation through IL17 and TNF production. Kim and colleagues have extended our knowledge of how activated MAIT cells are involved in lung inflammation through induction of proinflammatory cytokines, such as TNF, IL1β and IL8, in macrophages. Furthermore, in patients with ARDS, circulating MAIT cells produce a significant amount of IL17, which is more increased in BALF, suggesting an immunepropagative role of MAIT cells in the acute exudative phase of ARDS. There are several considerations when interpreting these findings. Although accumulating data implicate the clinical relevance of MAIT cells in ARDS, it is unclear how these findings can be incorporated into clinical practice. Kim and colleagues have suggested that activated MAIT cells migrate into the lung and potentiate macrophage activation via Th17type cytokines. However, a previous study underscored that the production of Th1 cytokines in MAIT cells is also crucial for the activation of macrophages. Among activation markers, including PD1, lymphocyteactivation gene 3 (LAG3) and CD69, PD1 expression on MAIT cells was inversely correlated with the frequency of MAIT cells in patients with ARDS. Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea