Research ArticleT CELLS

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

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Science Immunology  05 Jul 2019:
Vol. 4, Issue 37, eaav8995
DOI: 10.1126/sciimmunol.aav8995

Human resident memory T cells hit the road

Skin and other barrier tissues are home to long-lived tissue-resident memory T cells (TRM) that function as sentries capable of rapidly responding to previously encountered antigens. Klicznik et al. investigated the relationship between human skin CD4+ TRM and human blood CD4+ memory T cells expressing skin-homing markers by comparing immunophenotypes, gene expression, and T cell receptor sequences. Shared phenotype, function, and clonotypes between blood and skin CLA+CD103+CD4+ T cells indicated that blood CD4+CLA+CD103+ T cells were previously skin resident. Analysis of immunodeficient mice bearing human skin xenografts revealed that human skin CD4+ TRM can exit the skin, reenter the circulation, and home to secondary human skin sites. These findings establish that there is basal recirculation of human CD4+ skin TRM. See the related Focus by Carbone and Gebhardt.


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+CD69CD103+ 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.

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