90 JOURNAL OF COSMETIC SCIENCE FRONTIERS OF SCIENCE AWARD LECTURE SPONSORED BY COSMETICS AND TOILETRIES© T Cells, Skin Immunosurveillance, and the Human Immune Response Thomas S. Kupper, MD Harvard Medical School, Boston, MA The immune system is charged with protecting the host from infectious agents. Such agents are encountered at interfaces with the environment, and the skin is our largest of these interfaces. Immunity can be thought of as having two components--the Innate Immune System and the Acquired Immune System. Innate Immunity is phylogenetically ancient and elements of it can be found in insects and plants. In human skin, protein mediators such as defensins (which directly kill bacteria), cytokines, and complement are released when skin is injured. These events recruit leukocytes to the compromised integument and optimize host defense. The Innate Immune System, however, cannot "learn"-•each response is identical to the previous one, both qualitatively and quantitatively. In contrast, the Acquired Immune System can change and adapt, developing what is tantamount to "memory". A much more recent evolutionary development, Acquired Immunity developed about the same time as vertebrates in associated with longer life spans. Acquired Immunity is based upon cells with antigen receptors--B cells and T cells. The reshuffling of segmentss of genes during development generates billions of different antigen receptor sequences. For example, T cells that develop in the thymus express receptors composed of ct[3 or 78 chains, and each T cell has a T cell receptor with a unique sequence. Antibodies (B cell receptors) recognize tertiary, three-dimensional conformations of proteins. T cell receptors, on the other hand, recognize peptides of 8-20 amino acids bound to Major Histocompatibility Complex (MHC) molecules. Class I MHC molecules, such as HLA-A, B, and C bind peptides derived from the cytoplasm (both self and viral peptides) and present antigen to CD8+ T cells. Class II MHC molecules, such as HLA-DR and DQ bind peptides derived from proteins internalized from the extra cellular space (e.g., from bacteria or fungi), and present antigen to CD4+ T cells. HLA molecules are expressed at highest levels on dendritic cells, which also express costimulatory molecules that help maximally activate T cells. When a T cell's antigen receptor encounters a dendritic cell's HLA molecule binding the correct antigenic peptide, the T cell becomes activated by antigen. If this is the first time that the T cell h as seen its specific antigen, the T cell proliferates, and one cell gives rise to thousands of progeny. Some of these progeny survive for many years. This clonal expansion means that more antigen specific T cells are available to respond the next time such an antigen is encountered. If this antigen is from a pathogenic bacterium, then this immunologic memory serves host defense. With so •aaany different T cell receptors, how doex the i•nmune system ever get the right T cell to the right place st tb, e right time? NaYve T cells, which have never encountercd antigen, are not allowed to roam freely in the body. Rather, they recirculate between blood and lymph nodes, specialized organs that concentrate lymphatic drainage from large surface areas interfacing the environment. This recirculation is dependant on the expression of specialized cell surface molecules on both naive T cells and lymphatic vessels. Dendritic cells in skin, including epidermal Langerhans cells, internalize pathogens and "process" their proteins into peptides, which are expressed on MHC molecules. During this process, many of these dendritic cells migrate from skin to lymph node via afferent lymphatics. NaYve T cells are channeled through these lymph nodes, and thus the environment is effectively concentrated in an anatomic area in which naYve T cells are abundant. This is an efficient means of immunosurveillance of skin, performed in the draining lymph node. Another form of immunosurveillance depends upon the ability of certain T cells to exit blood vessels in skin. These T cells have special "skin homing" molecules expressed on their surface that

2002 ANNUAL SCIENTIFIC MEETING 91 interact with counter receptors expressed prominently in both normal and inflamed skin. CLA, or cutaneous lymphocyte antigen, is a glycoprotein expressed predominantly on skin homing T cells. Along with chemokine receptors CCR4 and CCR10, CLA initiates the process of T cell extravasation specifically in skin. Interestingly, CLA is expressed during the expansion and differentiation of a recently activated naive T cell in a skin draining lymph node. There is something unique about the microenvironment of a skin draining lymph node because CLA is not expressed by T cells that are first activated in other anatomic lymph node microenvironments (e.g., GI tract, lung). Skin homing memory and effector T cells use CLA to "tether", or bind under flow conditions, to E and P selectin expressed on skin post capillary venules. Again using CLA-selectin interactions, the T cells rolls along the surface of the vessel, exposing its cell surface receptors to ligands expressed on the endothelial wall. Chemokines bound to the wall of the vessel activate the T cell through chemokines receptors, leading to integ-rin activation and firm adhesion between LFA-1 on the T cell and ICAM-1 on the endothelium. This is followed by flattening of the T cell and transendothelial mi•ation through the vessel wall into the dermis. In this location, the T cell can respond to chemotactic gradients. This T cell can also recognize antigen presented to it by dendritic cells in the dermis. Effector T cells produce cytokines when they are activated, and these fall into two general categories. Type I cytokines include •N7 and TNFot, and induce inflammation. Type 2 cytokines include IL-4, IL-5, and IL-13--these cytokines promote allergic responses, characterized by eosinophil and mast cell activation. In both cases, these T cell cytokines are designed to amplify the type of inflammatory response best designed to eradicate the invading pathogen. Most of the time, this elegant system works very well. T cell mediated inflammatory skin diseases occur when the control of this system breaks down. For example, in allergic contact dermatitis, the immune system inappropriately recognizes innocuous chemicals as pathogens, and a population oft cells specific for these chemicals or their modifications is generated. In atopic dermatitis, innocuous environmental antigens, such as those derived from house dust mite, provoke a hyperresponsive skin homing T cell response, here dominated by type 2 cytokine production. In psoriasis, it is thought that the immune system has generated a robust response to an autoantigen in skin in this case, type I cytokines dominate. Cutaneous T Cell Lymphoma is a malignancy of the skin homing memory T cell. In all cases, successful therapies target, directly or indirectly, the skin homing effector and memory T cell. In the future, this research will guide a variety of endeavors that have general biomedical importance. Understanding organ specific T cell t-•, 'uing is critical for making effective cancer vaccines. The ability to generate tumor specific T cells in vitro that can also home appropriately in vivo would change our ability to treat many cancers. T cell trafficking is central not only to cutaneous immunity, but to the success of the human immune response in general.