Unconventional immune cells in the gut mucosal barrier: regulation by symbiotic microbiota

The mammalian gut is the most densely colonized organ by microbial species, which are in constant contact with the host throughout life. Hosts have developed multifaceted cellular and molecular mechanisms to distinguish and respond to benign and pathogenic bacteria. In addition to relatively well-characterized innate and adaptive immune cells, a growing body of evidence shows additional important players in gut mucosal immunity. Among them, unconventional immune cells, including innate lymphoid cells (ILCs) and unconventional T cells, are essential for maintaining homeostasis. These cells rapidly respond to bacterial signals and bridge the innate immunity and adaptive immunity in the mucosal barrier. Here, we focus on the types and roles of these immune cells in physiological and pathological conditions as prominent mechanisms by which the host immune system communicates with the gut microbiota in health and diseases. This study highlights the essential role of microbiota in regulating the maintenance and function of ILC subsets and unconventional T cells in the gut. Microbial colonization influences cytokine production, affecting ILC function in barrier maintenance and protection against pathogens. Additionally, microbiota-derived antigens shape MAIT and iNKT cell populations, with their activity finely regulated by a combination of metabolites and local cytokines influenced by the microbiota. Understanding these interactions could lead to innovative strategies for enhancing gut health and effectively treating immune-mediated diseases.