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Homing and function of human skin γδ T cells and NK Cells: relevance for tumor surveillance

Ebert, L. M., Meuter, S. and Moser, Bernhard ORCID: 2006. Homing and function of human skin γδ T cells and NK Cells: relevance for tumor surveillance. The Journal of Immunology 176 (7) , pp. 4331-4336. 10.4049/jimmunol.176.7.4331

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Normal (noninflamed) human skin contains a network of lymphocytes, but little is known about the homing and function of these cells. The majority of αβ T cells in normal skin express CCR8 and produce proinflammatory cytokines. In this study we examined other subsets of cutaneous lymphocytes, focusing on those with potential function in purging healthy tissue of transformed and stressed cells. Human dermal cell suspensions contained significant populations of Vδ1+ γδ T cells and CD56+CD16− NK cells, but lacked the subsets of Vδ2+ γδ T cells and CD56+CD16+ NK cells, which predominate in peripheral blood. The skin-homing receptors CCR8 and CLA were expressed by a large fraction of both cell types, whereas chemokine receptors associated with lymphocyte migration to inflamed skin were absent. Neither cell type expressed CCR7, although γδ T cells up-regulated this lymph node-homing receptor upon TCR triggering. Stimulation of cutaneous Vδ1+ γδ T cell lines induced secretion of large amounts of TNF-α, IFN-γ, and the CCR8 ligand CCL1. In contrast to cutaneous αβ T cells, both cell types had the capacity to produce intracellular perforin and displayed strong cytotoxic activity against melanoma cells. We therefore propose that γδ T cells and NK cells are regular constituents of normal human skin with potential function in the clearance of tumor and otherwise stressed tissue cells. Under conditions of homeostasis, human skin contains an extensive network of leukocytes, including dendritic cells (DCs),3 T cells, NK cells, mast cells, and macrophages (1, 2, 3). These leukocytes presumably function together in maintaining skin integrity by continuously surveying for the presence of foreign Ags or signs of cellular stress. The best-characterized mechanism of skin protection involves cutaneous DCs (Langerhans cells and dermal DCs), which migrate to skin-associated LNs for the initiation of tolerance or, in the case of skin infection, antimicrobial immune responses (4, 5). In this manner, microbe-specific T cells acquire cell surface molecules for guidance to affected skin to combat local infectious agents. Address cues for effector T cell migration to inflamed skin include E-selectin ligand (known as cutaneous lymphocyte-associated Ag/CLA in humans), as well as certain receptors for chemokines expressed in inflamed skin, including CCR4, CCR6, and CCR10 (6, 7, 8, 9). Thus, the mechanisms by which effector T cells are recruited from blood to inflamed skin are relatively well understood. In contrast, we are just beginning to understand the migration properties and function of T cells and other lymphocytes within healthy tissue (10, 11). We recently identified the chemokine receptor CCR8 as a specific marker of αβ T cells present in normal skin and demonstrated that CCL1/I-309, the unique ligand for CCR8, was constitutively produced at strategic sites in noninflamed skin (12). These cutaneous αβ T cells secreted large amounts of proinflammatory cytokines and may thus contribute to memory responses after contact with previously encountered Ags. However, αβ T cells are unlikely candidates for surveillance against tumors and stressed tissue cells (12). Therefore, we turned our attention to γδ T cells and NK cells. In contrast to αβ T cells, γδ T cells recognize Ags without the need for processing and presentation by classical MHC molecules (13, 14). The major subset of γδ T cells in human peripheral blood expresses the Vδ2 gene segment and recognizes nonpeptide Ags of mostly microbial origin. In contrast, most γδ T cells in epithelial tissues express the Vδ1 gene segment and respond to stress-associated factors, including heat shock proteins and the MHC-related molecules MHC-I-related protein A (MICA) and MHC-I-related protein B (MICB), which are induced on tumor and virus-infected cells (13, 14, 15, 16). NK cells similarly recognize abnormal cells using a repertoire of receptors that detect stress-associated molecules as well as the loss of surface MHC protein (17). Murine skin harbors a major population of Vδ1+ γδ T cells, known as dendritic epidermal T cells (DETCs), which appear to play a critical role in tumor surveillance, as evidenced in γδ T cell-deficient mice (18, 19). Surprisingly, however, a counterpart of DETCs does not exist in human epidermis (1), and it is thus unclear what types of lymphocyte mediate equivalent immune surveillance functions in human skin. In this study we demonstrate that normal human dermis contains distinct populations of γδ T cells and NK cells, both of which express receptors for homing to noninflamed skin and for recognition of allogeneic tumor cells. Together, these cells are likely to make a unique contribution to the elimination of cutaneous tumor and otherwise stressed cells.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of Acceptance: 17 January 2006
Last Modified: 21 Oct 2022 07:38

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