Depleting CD103⁺ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa

The oral mucosa is a frontline for microbial exposure and juxtaposes several unique tissues and mechanical structures. Based on parabiotic surgery of mice receiving systemic viral infections or co-housing with microbially diverse pet shop mice, we report that the oral mucosa harbors CD8⁺ CD103⁺ resident memory T cells (T_RM), which locally survey tissues without recirculating. Oral antigen re-encounter during the effector phase of immune responses potentiated T_RM establishment within tongue, gums, palate, and cheek. Upon reactivation, oral T_RM triggered changes in somatosensory and innate immune gene expression. We developed in vivo methods for depleting CD103⁺ T_RM while sparing CD103^neg T_RM and recirculating cells. This revealed that CD103⁺ T_RM were responsible for inducing local gene expression changes. Oral T_RM putatively protected against local viral infection. This study provides methods for generating, assessing, and in vivo depleting oral T_RM, documents their distribution throughout the oral mucosa, and provides evidence that T_RM confer protection and trigger responses in oral physiology and innate immunity.