A T lymphocyte's ability to home, ie to recognize, bind and extravasate through vascular endothelium, is a critical element in its functional repertoire. This homing is a flexible, yet precisely regulated, process that provide the various tissues of the body with lymphocyte subsets appropriate to their immunologic """"""""needs"""""""". The applicant has previously shown that immune reactions in the skin are predominantly mediated by a specific subset of memory/effector T cells that express the skin-selective homing receptor (HR), cutaneous lymphocyte associated antigen (CLA). The applicant hypothesizes that the level of T cell CLA expression, and consequently the degree of skin-selective homing, is regulated by specific microenvironmental factors during the virgin to memory/effector T cell transition in secondary lymphoid tissues, primarily lymph nodes draining skin, and subsequent memory/effector T cell re-activation in skin. In the applicant's model, repeated antigen (Ag)-induced activation in these microenvironments results in differentiating T cells consistently receiving signals that upregulate CLA, and down-regulate tissue-selective HR to other sites, thereby creating an Ag-specific, """"""""homing-polarized"""""""" effector subset, analogous to the polarized """"""""TH1 vs TH2"""""""" cytokine-defined subsets, which are similarly generated during memory/effector T cell differentiation. Under normal conditions, this skin-selective homing mechanism likely acts to focus effector T cells specific for predominantly skin-invading pathogens to the skin, thereby increasing the efficiency of immune responses against such organisms. However, this same mechanism may also be used by pathogenic, allergen-specific, effector T cells, and thus may participate in the pathogenesis of chronic inflammatory skin diseases, such as allergic contact dermatitis (ACD), atopic dermatitis (AD). In this application, it is proposed to use multiparameter flow cytometry, quantitative RT-PCR, and other immunologic assays to determine: 1) whether circulating allergen-specific CD4+ memory/effector T cells in ACD and AD are """"""""polarized"""""""" with respect to their expression of CLA vs. mucosal HR and/or their ability to synthesize cytokines (interferon-gamma vs interleukin-2 (IL-2) vs IL-4 vs IL-5); 2) the role of microenvironmental factors (particularly the cytokines IL-12, IL-4, IL-6, IL-10, and transforming growth factor-beta1 [TGF-b1]) in coordinately regulating HR expression and cytokine synthesis capabilities during CD4+ T cell differentiation (both in vitro models of this process, and in actual human lymphoid tissues); 3) whether differentiation HG regulation plays a role in determining the clinical expression of atopy in the skin (AD) vs. the lung (asthma); and 4) whether an inherent, abnormal regulation of HR expression and cytokine synthesis plays a role in determining an individual's susceptibility to chronic ACD or AD. Taken together, these studies should give new insights into the pathophysiology of chronic inflammatory skin disease, and will provide an invaluable data base for the development of novel therapeutic strategies for these disorders based on the pharmacologic manipulation of skin-selective T cell homing.
