During adaptive immune responses, dendritic cells activate T cells and endow them with specific homing properties. Mechanisms that 'imprint' specific tropisms, however, are not well defined. We show here that 1,25(OH)(2)D(3), the active form of vitamin D3, signaled T cells to express CC chemokine receptor 10, which enabled them to migrate to the skin-specific chemokine CCL27 secreted by keratinocytes of the epidermis. In contrast, 1,25(OH)(2)D(3) suppressed the gut-homing receptors alpha4beta7 and CCR9. Vitamin D3, the inactive prohormone naturally generated in the skin by exposure to the sun, was processed by dendritic cells and T cells to the active metabolite, providing a mechanism for the local regulation of T cell 'epidermotropism'. Our findings support a model in which dendritic cells process and 'interpret' locally produced metabolites to 'program' T cell homing and microenvironmental positioning.

SUMMARYPsoriasis is a common autoimmune skin disease characterized by T cell-mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA-Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2·5 times higher disease risk than heterozygotes. Published data indicate that CD8 + T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8 + T cells, and probably also of CD4 + T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4 + T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that crossprimed CD8 + T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8 + T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4 + , CD8 + T cells and cross-presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4 + and CD8 + T cells.

Lymphocytes are imprinted during activation with trafficking programs (combinations of adhesion and chemoattractant receptors) that target their migration to specific tissues and microenvironments. Cytokines contribute, but, for gut and skin, evolution has cleverly adapted external cues from food (vitamin A) and sunlight (ultraviolet-induced vitamin D3) to imprint lymphocyte homing to the small intestines and T cell migration into the epidermis. Dendritic cells are essential: they process the vitamins to their active metabolites (retinoic acid and 1,25(OH) 2 D3) for presentation with antigen to lymphocytes, and they help export environmental cues through lymphatics to draining lymph nodes, to program the trafficking and effector functions of naive T and B cells.Leukocyte chemoattractant and adhesion receptors direct the systemic trafficking and the microenvironmental positioning of the cells of the immune system and control cell-cell interactions that regulate leukocyte activation in inflammation, immunity and immune pathology [1][2][3][4][5] . Tissue-and inflammation-selective interactions of circulating lymphocytes and other leukocytes with specialized vascular endothelium mediate leukocyte recruitment in an active, multistep process involving tethering (mediated primarily by selectins and α 4 integrins) and rolling (in which the enzyme vascular adhesion protein-1 (ref. 6 ), the lectinlike oxidized LDL receptor-1 (ref. 7 ) and the hyaluronate receptor CD44 can also participate 8,9 ); chemoattractant-induced rapid integrin activation (mediated by chemokine and other G protein-coupled receptors); activation-dependent firm arrest on the vessel wall (mediated by integrins, especially β 2 integrins); and diapedesis in response to chemoattractants. Recruitment can be regulated at any or all of these points, and the implications of this for combinatorial diversity, specificity, and mechanistic resiliency in leukocyte trafficking have been discussed in detail 4 .From the perspective of regional physiology and pathology, selective trafficking provides a mechanism for segregating the specialized immune response modalities characteristic of cutaneous versus systemic or intestinal immune responses and for targeting specialized lymphocyte subsets to particular immune microenvironments, such as the B or T cell zones in lymphoid tissues or the epithelial or subcutaneous tissues in the skin. From the perspective of therapeutics, tissue-and microenvironment-specific homing represents an attractive target for the manipulation of localized immune and inflammatory responses.Recently, substantial progress has been made in identifying cells and molecular mediators that are responsible for imprinting specialized trafficking programs.