Figure 4. Immunosurveillance features of T_RM include prolonged tissue residence, secretion of cytotoxic molecules, an activated transcriptional profile, intra-epithelial trafficking and self-organizational behavior.

(A) Immunohistochemical evidence of perforin granules (green) within multiple tissue-resident CD8+ T cells from human genital skin biopsies at a timepoint 8 weeks post lesion healing when HSV-2 antigen is not detected in tissue (reference 14) (B) Transcriptional evidence of an activated state in CD8+ T cells from human genital skin biopsies at a timepoint 8 weeks post healing when HSV-2 antigen is not detected in tissue. Gene expression is compared between CD8+ T cells detected at the dermal-epidermal junction (presumed T_RM) versus control cells from the same individual with red and green indicating up and down regulated genes respectively (reference 14) (C) Intravital imaging evidence that T_RM express dendritic arms and patrol extensively within but not beyond local micro-environment (reference 46). The left panel is an initial frame of a time-lapse movie in which the branching nature of T_RM in murine flank skin is evident. The right panel is superimposed frames taken every 3 minutes over 7.5 hours showing that a majority of the local tissue region is patrolled. However, over more than a year, cells rarely migrate more than 5 mm from their starting location. (D) Immunohistochemistry evidence that T_RM demonstrate self-organizational behavior in human genital skin with clustering of CD8+ T cells at the dermal epidermal junction. We determined that the ratio of CD8+ T cells to epithelial cells within the square regions follows an exponential slope on a rank order distribution, indicating a strict slope to CD8+ T cell structure in tissue.