Leukocyte Homing To The Skin

While it is clear that immune responses in the skin have many unique characteristics, homing of lymphocytes to the skin is poorly understood. Nai've T cells that encounter antigen in skin-associated lymph nodes develop into skin-homing effector T cells. y5 T cells have been shown to play an important role in innate immunity. Particularly, y5 T cells have been shown to localize in large numbers to the epidermis of mice and cattle but not humans L156], In the skin, these y5 intraepithelial T cells show distinct dendritic cell morphology and are known as dendritic epidermal T cells [156], However, little is known about trafficking of y8 T cells to the skin. Most work on the role of chemokine mediated T cell trafficking to the skin focuses on a(3 T cells.

Skin-homing T cells are characterized by their expression of cutaneous lymphocyte antigen (CLA), an epitope which functions as a homing receptor for T cells in inflamed skin. Picker et al. [157] originally showed that the majority of T lymphocytes in inflammatory skin lesions expressed CLA, whereas very few T cells expressed CLA in extracutaneous sites of inflammation. The vascular CLA receptor, E-selectin, is highly expressed on endothelial cells in inflamed skin and mediates initial cell contact (tethering) and rolling. However, migration directed by CLA/E-selectin alone is insufficient to explain homing of memory T lymphocytes to skin. Neutrophils also express CLA but do not migrate to the skin and E-selectin is commonly expressed on extracutaneous epithelium [ 16]

The chemokine receptor CCR4 is involved in homing of cutaneous T memory lymphocytes to the vascular endothelium at cutaneous sites of inflammation. Systemic a4(37 memory T cells in the blood, including all skin homing CLA+ T cells, express CCR4 and respond to its ligands CCL17/TARC and CCL22/MDC. In addition, Campbell et al. [122] found CCR4+ lymphocytes in chronically inflamed skin, but not in the gastrointestinal lamina propria and further demonstrated CCL17/TARC expression in cutaneous venules and skin epithelium but not mucosal epithelium. CCL17/TARC and CCL27/CTACK (cutaneous T cell-attracting chemokine) are expressed in the skin and can recruit CLA+ memory T cells, but not naive T cells, B cells, neutrophils or monocytes [158]. CCL27/CTACK mRNA is constitutively expressed in mouse epidermis and human keratinocytes, but is absent in all other tissues. This suggests that CCL27/CTACK plays a role in specific trafficking during normal immune surveillance, although its induction by proinflammatory cytokines suggests a role in inflammatory processes as well. Most recently, circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells, and fibroblasts were shown to express the CCL27/CTACK receptor CCR10. Neutralization of CCL27/CCR10 binding disrupts lymphocyte homing to the skin and can suppress allergen-induced skin inflammation [159], However, Reiss et al. [160] recently demonstrated that blocking of either CCR4 or the CCR10 ligand CCL27/CTACK has no effect on T cell homing to inflamed skin, but blocking of CCL27/CTACK abrogated skin recruitment of CCR4 deficient T cells, showing that these receptors may have overlapping and redundant roles in T cell recruitment to the skin. In addition to T cells, Langerhans cells in the epidermis play a critical role in the immune network. Langerhans cells are immature dendritic cells which uptake and process foreign antigen in the skin, however they also traffic to the skin under homeostatic conditions. CCR6has been shown to mediate trafficking of Langerhans cells to the epidermis in response to Mip-3a produced locally by keratinocytes [161].

It is becoming clear that a number of chemokine/receptors such as CCR4, CCR6 and CCR10, in conjunction with CLA contribute to the tissue-specific lymphocyte and dendritic cell homing in normal and inflamed cutaneous sites. Such chemokines and adhesion molecules are critical players in the immune network.

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