MicroRNA‐managing the development of MAIT cells

Mucosal-associated invariant T (MAIT) cells respond to antigens derived from the riboflavin biosynthesis pathway, which occurs in bacteria and yeast but not mammalian cells. These riboflavinderived antigens are presented to MAIT cells in association with the molecule MR1, an MHC class-I-like antigen-presenting molecule that is highly conserved between mammals. Upon activation, MAIT cells rapidly produce proinflammatory cytokines, suggesting that the MR1-MAIT cell axis is an important component in host immunity for detecting bacterial metabolism and infection. MAIT cells branch from the mainstream T cell developmental pathway within the thymus, but the factors that control their development are not wellunderstood. In this issue, Winter et al. demonstrate that microRNA 181a/b-1 plays a key role in regulating the early differentiation of MAIT cells. MAIT cells share similar unconventional, innate-like attributes with the more extensively studied CD1d-lipid-reactive natural killer T (NKT) cells. They both utilize semiinvariant T cell receptors (TCRs) to recognize non-peptide antigens presented by MHC-I-like molecules (MR1 and CD1d, respectively), and are selected by CD4CD8 cortical thymocytes. This channels them along a developmental program in the thymus where the expression of the transcription factor PLZF distinguishes them from conventional peptide-MHC-reactive T cells. The development of MR1-tetramer reagents loaded with the riboflavin-derivate antigen 5-(2-oxopropylideneamino)-6D-ribitylaminouracil has enabled direct studies of MAIT cells in mice and humans, leading to rapid advances in our understanding of the biology of these cells. This included developmental studies that revealed a three-step maturation pathway in humans and mice. In mice, these steps are defined as immature stage 1 (CD24CD44 ), intermediate stage 2 (CD24 CD44 ) and mature stage 3 (CD24 CD44) MAIT cells (Figure 1). One factor that was found to be essential for MAIT cell development was the enzyme Drosha. Drosha, along with Dicer, are RNAseIII enzymes responsible for the generation of canonical mature micro-RNAs (miRs). In the absence of Drosha, MAIT cell development reached stage 1 but did not efficiently progress beyond this point, suggesting a key role for miRs in the intrathymic maturation of these cells. miRs are non-coding posttranscriptional gene regulators involved in diverse biological events ranging from immune development to carcinogenesis, and act predominantly by destabilizing mRNA or inhibiting protein translation. Knowing that Drosha was important for intrathymic MAIT cell development, Winter et al. sought to examine which miRs were controlling this process. Based on previous findings that a specific pair of miRs, miR-181a/b-1, were instrumental for intrathymic NKT cell development, they examined the role of these same miRs in MAIT cell development and function. Using a toolbox of miR-181a/b-1 / , RAG1 reporter, and bone marrow chimeric MAIT TCRa transgenic x miR-181a/ b-1 / mouse models, they showed that miR-181a/b-1 are intrinsically required for MAIT cell development. Deletion of miR-181a/b-1 mirrored the MAIT cell developmental defect in Drosha / mice (Figure 1). Thus, as previously reported in Drosha / mice, in miR-181a/b-1 / mice there was a major defect in MAIT cell development but some residual MAIT cells, primarily immature stage 1 cells, were still detectable in the thymus. These were present in similar numbers between the Drosha / , miR-181a/ b-1 / and wild-type mice, indicating that miR-181a/b-1 are not required for the initiation of the MAIT cell differentiation pathway. While stage 2 MAIT cells were reduced in miR-181a/ b-1 / mice, the greatest impact was on stage 3 MAIT cells, which suggests that miR-181a/b-1 are important for maturation from stage 1 to 2 and from stage 2 to 3. The authors also showed that MAIT cells normally begin intrathymic proliferation at stage Correspondence Dale I Godfrey, Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia. E-mail: godfrey@unimelb.edu. au