LAUSR

With inflammatory bowel disease, such as Crohn’s disease and colitis, being heavily dependent on immune cell function, the mechanisms controlling aberrant immune cell activity in the gut have become an area of interest for biomedical research. Although the etiology of inflammatory bowel disease remains unknown, it is caused by a combination of genetic, environmental and microbial factors leading to altered immune cell functions in the gut. Developing and maintaining tolerance are necessary in preventing immune-mediated disorders including inflammatory bowel disease. Foxp3 (forkhead box P3 transcription factor)–expressing regulatory T cells (Tregs) are critical mediators of immune tolerance to selfand non-self-antigens and can arise both in the thymus (i.e. thymusderived Tregs) and extrathymically in the periphery [i.e. peripherally induced Tregs (pTregs)]. While thymus-derived Tregs promote immune tolerance to self-antigens, pTregs play a major role in tolerance to foreign antigens. Although the developmental mechanisms promoting thymus-derived Treg development in the thymus, including the involvement of the thymic antigen-presenting cell (APC) autoimmune regulator (Aire) and medullary thymic epithelial cells (mTECs), are well established, the regulatory mechanisms governing pTreg development and tolerance to gut microbiota remain unclear. A recent study by Akagbosu and Tayyebi et al. has identified a new class of APC involved in pTreg development and establishing gut immune tolerance during early life. APCs promote central tolerance by participating in the removal of selfreactive T cells via negative selection, and by inducing thymus-derived Treg development in the thymus. Different types of APCs, including CD103 dendritic cells (DCs), programmed death ligand 1/2(PD-L1/2)–expressing DCs, CX3CR1 intestinal macrophages and major histocompatibility complex (MHC)II group 3 innate lymphoid cells (ILC3s), have been shown to promote immune tolerance in the gut by a variety of different mechanisms including pTreg development. In addition to these APCs, cells expressing retinoic acid–related orphan receptorgamma t (RORct), the master transcription factor for T helper type 17 cells, were also shown to play a role in gut immune tolerance. For example, Zhou et al. suggested that RORct cells in the intestine were a subset of ILC3s because of coexpression of the transcription factor ZBTB46, a gene highly expressed by Lti (lymphoid tissue-inducer)-like ILC3s. Interestingly, these ZBTB46 ILC3 cells were shown to be important for gut immune tolerance, as selective depletion of these cells rendered mice susceptible to enteric infection and intestinal inflammation. However, previous work by Brown et al. identified a subset of RORct-expressing cells thought to be a classical DC type 2 subset that expressed high levels of MHCII, CD86 and programmed death ligand 1 upon LPS exposure in vivo. The work by Akagbosu and Tayyebi et al. thus clarifies the identity of RORct-expressing cells as a unique subset of RORct MHCII APCs coined Thetis cells (TCs), critical for immune tolerance to the gut microbiota and prevention of intestinal inflammation during early life. Akagbosu and Tayyebi et al. have identified that the development of TCs coincides with pTreg expansion, suggesting the involvement of TCs in pTreg differentiation. Building on a previous finding that mice deficient in MHCII-restricted antigen presentation by RORct APCs do not establish tolerance to commensal bacteria and develop severe colitis, the authors explored a potential connection between RORct APCs and pTreg development in the gut during early life. The authors found that mice with a constitutive deletion of MHCII on RORct APCs exhibited a marked reduction in pTreg cells associated with an increase in inflammatory T helper type 17 cells. Correspondence Gopal Murugaiyan, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, 60 Fenwood Road, Boston, MA 02115, USA. E-mail: [email protected]