Virus-specific resident memory T cell networks sustain immunity in human oral mucosa

Durable protection against viral infections relies on tissue-resident memory T (T_RM) cells at pathogen entry sites. The oral cavity is a critical mucosal barrier frequently exposed to viral pathogens; however, the phenotypic characteristics and spatial organization of virus-specific T cells in the human oral mucosa remain poorly understood.

This study aimed to define how virus-specific T cells maintain long-term residency in the oral mucosa and to identify cellular interactions supporting their persistence.

We profiled predicted virus-specific T cells in the blood and oral mucosa of seven healthy individuals who recently recovered from SARS-CoV-2 infection. Single-cell RNA and T cell receptor sequencing, spatial transcriptomics, and immunofluorescence (IF) were used to define cell composition, localization, and interactions.

Cytomegalovirus-specific T cells were predominantly CD4⁺ effector memory T cells, whereas Epstein-Barr virus- and SARS-CoV-2-specific T cells were mainly CD8⁺ T_RM cells with cytotoxic features. Cell-cell communication analysis suggested that predicted virus-specific CD8⁺ T_RM cells were embedded in highly interactive signaling networks, receiving strong inputs from fibroblasts and dendritic cells. Spatial transcriptomics and IF confirmed close associations between CD8⁺ T_RM, fibroblasts, and dendritic cells.

Predicted virus-specific CD8⁺ T_RM cells appear to play a prominent role in the human oral mucosa, where supportive communication networks with fibroblasts and dendritic cells likely contribute to their persistence and long-term survival at this critical barrier site.