Transcription factors define tissue T cells: The immune system fights microbial invaders by maintaining multiple lines of defense. For instance, specialized memory T cells [resident memory T cells (T _rms )] colonize portals of pathogen entry, such as the skin, lung, and gut, to quickly halt reinfections. Mackay et al. now report that in mice, T _rms as well as other tissue-dwelling lymphocyte populations such as natural killer cells share a common transcriptional program driven by the related transcription factors Hobit and Blimp1. Tissue residency and retention of lymphocytes require expression of Hobit and Blimp1, which, among other functions, suppress genes that promote tissue exit. Science , this issue p. 459

Significance: Tissue-resident memory T cells (T _RM ) form in the skin where they are retained and can protect against subsequent infection. Using a combination of intravital imaging and mathematical modeling of skin T _RM that form after cutaneous herpes simplex virus 1 infection, we reveal that these memory T cells persist at the site of infection for the life of a mouse owing to slow random migration. We also report that T _RM compete with dendritic epidermal γδ T cells in skin for local survival signals, suggesting that T cells compete for space within an epidermal niche.