CD49a Expression Defines Tissue-Resident CD8 + T Cells Poised for Cytotoxic Function in Human Skin

Abstract

SummaryTissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon-γ, whereas CD8+CD49a− Trm cells produced interleukin-17 (IL-17). In addition, CD8+CD49a+ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8+CD49a+ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8+CD49a– Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8+ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

“…Transcriptional profiling has been reported for mouse CD8 + TRM in which CD8 + memory T cells isolated from a barrier site (skin, intestine or lung) were compared with spleen (Mackay et al, 2016; Mackay et al, 2013). In human studies, CD8 + TRM isolated based on CD103 expression from individual tissues (lung, skin) have been profiled in comparison to blood subsets (Cheuk et al, 2017; Hombrink et al, 2016). Here, we employed an innovative and comprehensive approach to assess differences in putative circulating and resident populations within tissues by directly comparing CD69 + memory subsets from a lymphoid and mucosal site (spleen and lung) with the corresponding CD69 − subset from each tissue as well as CD69 − TEM from blood for both CD4 + and CD8 + lineages.…”

“…We found phenotypic heterogeneity based on the core markers, particularly among CD4 + TRM, and additional tissue heterogeneity has been reported in CyTOF profiling of human tissue T cells (Wong et al, 2016). CD103 expression by mouse intestinal TRM (Bergsbaken and Bevan, 2015) and CD49a in human skin memory T cells (Cheuk et al, 2017), have been shown to delineate distinct functional capacities, and dissecting human TRM heterogeneity will be an important area of focus in future studies.…”

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

“…Transcriptional profiling has been reported for mouse CD8 + TRM in which CD8 + memory T cells isolated from a barrier site (skin, intestine or lung) were compared with spleen Mackay et al, 2013). In human studies, CD8 + TRM isolated based on CD103 expression from individual tissues (lung, skin) have been profiled in comparison to blood subsets (Cheuk et al, 2017;Hombrink et al, 2016). Here, we employed an innovative and comprehensive approach to assess differences in putative circulating and resident populations within tissues by directly comparing CD69 + memory subsets from a lymphoid and mucosal site (spleen and lung) with the corresponding CD69 − subset from each tissue as well as CD69 − TEM from blood for both CD4 + and CD8 + lineages.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…59 In human skin, the presence or absence of CD49a expression can divide T RM s into IFN-γ or IL-17-Producing cells and associated with type 1 or type 17 effector T cell-related disease settings. 62 However, the molecular and cellular control of the type 17 effector program in CD8 + T cells or T RM cells remains unclear.…”