A transmissible γδ intraepithelial lymphocyte hyperproliferative phenotype is associated with the intestinal microbiota and confers protection against acute infection

Intraepithelial lymphocytes expressing the gamma delta T cell receptor (gamma delta IELs) serve as a first line of defense against luminal microbes. Although the presence of an intact microbiota is dispensable for gamma delta IEL development, several microbial factors contribute to the maintenance of this sentinel population. However, whether specific commensals influence population of the gamma delta IEL compartment under homeostatic conditions has yet to be determined. We identified a novel gamma delta IEL hyperproliferative phenotype that is characterized by expansion of multiple Vgamma subsets. Horizontal transfer of this hyperproliferative phenotype to mice harboring a phenotypically normal gamma delta IEL compartment was prevented following antibiotic treatment, thus demonstrating that the microbiota is both necessary and sufficient for the observed increase in gamma delta IELs. Further, we identified two guilds of small intestinal or fecal bacteria represented by 12 amplicon sequence variants (ASV) that are strongly associated with gamma delta IEL expansion. Using intravital microscopy, we find that hyperproliferative gamma delta IELs also exhibit increased migratory behavior leading to enhanced protection against bacterial infection. These findings reveal that transfer of a specific group of commensals can regulate gamma delta IEL homeostasis and immune surveillance, which may provide a novel means to reinforce the epithelial barrier.