Protective and pathogenic roles of resident memory T cells in human skin disorders

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.

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Circulating CD4+ memory T cells give rise to a CD69+ resident memory T cell population in non-inflamed human skin

10.1101/490094 ◽

2018 ◽

Cited By ~ 2

Author(s):

Maria M Klicznik ◽

Ariane Benedetti ◽

Angelika Stoecklinger ◽

Daniel J Campbell ◽

Iris K Gratz

Keyword(s):

T Cells ◽

Candida Albicans ◽

T Cell ◽

Human Skin ◽

Cell Population ◽

Memory T Cells ◽

Humanized Mouse Model ◽

Normal Human Skin ◽

Memory T Cell ◽

Resident Memory T Cells

The blood of human adults contains a pool of circulating CD4+ memory T cells and normal human skin contains a CD4+CD69+ memory T cell population that produce IL17 in response to Candida albicans. Here we studied the generation of CD4+CD69+ memory T cells in human skin from a pool of circulating CD4+ memory T cells. Using adoptive transfer of human PBMC into a skin-humanized mouse model we discovered the generation of CD4+CD69+ resident memory T cells in human skin in absence of infection or inflammation. These CD4+CD69+ resident memory T cells were activated and displayed heightened effector function in response to Candida albicans. These studies demonstrate that a CD4+CD69+ T cell population can be established in human skin from a pool of circulating CD4+ memory T cells in absence of infection/inflammation. The described process might be a novel way to spread antigen-specific immunity at large barrier sites even in absence of infection or inflammation.

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

10.1101/361758 ◽

2018 ◽

Cited By ~ 1

Author(s):

M. M. Klicznik ◽

P. A. Morawski ◽

B. Höllbacher ◽

S. R. Varkhande ◽

S. Motley ◽

...

Keyword(s):

T Cells ◽

Human Skin ◽

Healthy Subjects ◽

Memory T Cells ◽

Xenograft Model ◽

Lymphoid Tissues ◽

Distant Tissue ◽

Resident Memory T Cells ◽

Skin Xenograft

AbstractTissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues where they provide front-line 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 re-enter the circulation and potentially migrate to distant tissue sites have been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69 and exit the tissue.Additionally, 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 re-enter circulation, and migrate to secondary human skin sites where they re-assume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.One Sentence SummaryHuman CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy subjects, and these cells can seed distant skin sites.

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