Human CD4 ⁺ CD103 ⁺ cutaneous resident memory T cells are found in the circulation of healthy individuals

Abstract

Tissue-resident memory T cells (TRM) persist locally in nonlymphoid tissues where they provide frontline defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69, which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to reenter the circulation and potentially migrate to distant tissue sites has been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can down-regulate CD69 and exit the tissue. In addition, we identified a skin-tropic CD4+CD69−CD103+ population in human lymph and blood that is transcriptionally, functionally, and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can reenter circulation and migrate to secondary human skin sites where they reassume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.

Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma

“…Although not investigated here directly, we hypothesize that neoplastic clones do not migrate unidirectionally from the blood to the skin. Recent findings that downregulation of CD69 enables skin resident memory cells to exit the tissue and to recirculate 52 indicates that neoplastic cells in MF should also be able to re-enter the circulation and contribute to the pool of circulating neoplastic clones. This mechanism is reminiscent of the phenomenon of tumor self-seeding 36,53 where circulating metastatic cells colonize the primary tumor.…”

Transcriptional profiling and single-cell chimerism analysis identifies human tissue resident T cells in the human skin after allogeneic stem cell transplantation

“…While the overall blood T cell population displayed a resting functional state, the host blood CD8+ T cell population displayed a strong enrichment of proliferating T cells according to the proportion of cells within the G2/M phase. It remains scarcely investigated whether and how TRM cells exit their tissue of origin 10,19. Based on our cell cycle analysis, we speculate that preceding T cell activation might have mobilized them out of their respective tissues.…”

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…Recently, the dogma of T RM as a non-circulating subset was challenged by identifying a population of circulating CD4 + T RM in human blood, which was designated as "ex-T RM " [107]. These CD4 + ex-T RM express the skin homing and retention glycan cutaneous lymphocyte-associated antigen (CLA), have similar phenotypic and transcriptional attributes as skin resident CD4 + CD103 + CLA + T RM , and share a clonal origin with CD4 + CD103 + CLA + T RM in the skin, based on TCR sequencing [108]. Thus, these new data suggest that CD4 + T RM may reside in tissues for prolonged periods of time, but possibly not for all of their lifespan.…”