The body’s surfaces, such as the skin, mucosal tissues and epithelial linings, are not passive barriers but active immunological sites. These sites constantly sense and respond to environmental cues, maintain homeostasis with the microbiota, respond to pathogens and calibrate the systemic immune response. Breakdown in barrier immunity can lead to allergy, autoimmunity and systemic immune activation. Advances in next-generation sequencing in the 2000s were a turning point in our understanding of barrier immunology, enabling deeper insights into the complexity and immunological importance of the microbiota. More recently, the COVID-19 pandemic brought mucosal immunology into focus. Our established understanding of the mucosal immune response enabled the rapid development of effective treatments and was used to guide vaccine strategies. To provide an overview of recent advances in immunology at barrier sites, we have commissioned a series of Review articles, the first three of which are now published in the current issue of Nature Immunology.

In their Review, Daniel Kaplan, Laura Mackay and colleagues explore the latest developments in our understanding of the skin immune system, paying particular attention to skin-resident T cells. The skin is a dynamic barrier, populated by commensal microorganisms, as well as a complex immune landscape across the epidermis, dermis and hair follicles. Resident memory T cells in the skin are phenotypically and functionally diverse yet share a common gene signature across tissues — they mediate localized protection from infection and prevent cancer but are implicated in autoimmunity and allergy. Although initially defined as a resident population, recent work suggests that there is some recirculation between the skin and blood. Understanding the complexity of resident memory T cell subsets has led to advances in the use of biologics to treat vitiligo and psoriasis.

In another Review, Ken Cadwell and P’ng Loke discuss what happens during the early stages of a breakdown in the balance of the intestinal immune system. In genetically susceptible individuals, environmental perturbations, such as infection or changes to diet, disrupt symbiotic relationships with the microbiota and can result in the development of inflammatory bowel disease. The authors propose that a better understanding of the preclinical phase of inflammatory bowel disease and mechanisms of genetic and environmental interactions could better inform the development of personalized treatments.

The gastrointestinal tract contains its own dedicated nervous system, the enteric nervous system, often denote “the little brain of the gut”. In their Review, Guy Boeckxstaens and colleagues discuss the roles of neuron-associated macrophages in the development and inflammation of the gut. The crosstalk between the enteric nervous system and resident macrophages develops throughout life. Macrophages are crucial for the development and survival of neurons in the gut, and neuron-associated macrophages are transcriptionally and functionally different from gut mucosal macrophages, with neuronal signals controlling their identity. Loss of the neuro-supportive phenotype of gut macrophages may be involved in enteric neuropathy during aging and in diseases such as diabetes and inflammatory bowel disease.

In upcoming issues of Nature Immunology, Bart Lambrecht and colleagues will review the basic immunology of asthma, providing an update on mechanistic insights into the pathology of disease and the development of biologic treatments. T helper 2 (TH2) cells were once considered central to asthma pathogenesis, asthma is now recognized as a heterogenous disease, although 30% of adults with severe asthma have no easily identifiable endotype. Understanding the mechanisms and endotypes of asthma can help to inform personalized treatments — for example, type 2 biologics are most effective in individuals with type 2 biomarkers but are less effective in non-type 2 asthma.

As highlighted by this Reviews series, a breakdown in microbiome–immune homeostasis can result in serious inflammatory disease at the site of breakdown. The extensive effects of the microbiome on the local and systemic immune system are discussed by A. Sloan Devlin and colleagues in their Review. The authors highlight how microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, can influence T cell development, T cell activation, memory and exhaustion.

Antigen-presenting cells (APCs) are crucial in maintaining intestinal homeostasis and protection from pathogens. In their Review, Tilman Hoelting and Chrysothemis Brown discuss the recently identified population of RORγt+ APCs. Classical dendritic cells, B cells, monocytes and macrophages are thought to be professional APCs, and their roles in shaping T cell-mediated immunity and tolerance are clear. RORγt+ APCs are transcriptionally distinct from dendritic cells and group 3 innate lymphoid cells (ILC3s) and express gene programs associated with antigen processing, presentation, co-stimulation and migration, and may have a role in the generation of peripheral regulatory T cells.

Finally, in their Review, Iliyan Iliev et al. discuss the interactions between the microbiota and the mucosal immune system from infancy to adulthood, highlighting effects in health and disease. The neonatal gut microbiota is essential for the development of the gut and the profound changes that occur at weaning. The authors also outline the complex role of fungi, viruses and protozoa in immunity and inflammation and how host microbiome interactions can be harnessed to promote therapeutic efficacy of a range of treatments, including immune checkpoint inhibition and the treatment of autoimmune and inflammatory conditions.

As our understanding of barrier immunology continues to evolve, the importance of maintaining balance remains clear. Insights into the how immunology at barrier sites intersects with emerging fields, such as neuroimmunology, immunometabolism and immunosenescence, will shape future research directions. Subsequent work has the potential to inform the development of personalized medicine for the treatment of allergies, autoimmunity and cancer. These Reviews can be found at https://www.nature.com/collections/aacheecdch and in future issues of Nature Immunology.