Costimulatory molecules have been demonstrated to play a central role in the regulation of T cell activation. The skin is a major protective barrier, being a site where foreign antigens are initially encountered. The regulated expression of costimulatory molecules on cells in the skin that facilitate antigen presentation to T cells is crucial to the understanding of T cell function in the skin. Recently, it has been suggested that B7 and/or B7-like molecules may be important for T cell activation in the skin microenvironment. Several studies indicate that Langerhans cells can express B7. However, it is not clear whether B7 or a B7-like molecule is expressed by keratinocytes. The major objective of this project is to investigate the role of B7:CD28/CTLA4 pathway in T cell activation in the skin. To gain insight into the role of B7 in T cell activation and tolerance in vivo, we have successfully generated a mouse strain deficient in B7 expression using homologous recombination and embryonic stem cell technologies. The B7 deficient mouse strain can serve as a unique tool for the study of the role of B7 in cutaneous immunity and for the identification and characterization of additional CD28/ CTLA4 ligands. A comparison of the ability of keratinocytes and Langerhans cells from wild type and B7 deficient mice to activate T cells should clarify the role of B7 in T cell activation by antigen presenting cells in the skin. In addition, B7 deficient keratinocytes and Langerhans cells will be a useful tool for identifying novel B7-like molecules in the skin microenvironment. An understanding of the physiologic functions of B7 is crucial for the design of rational therapeutic approaches involving manipulation of costimulatory signals.
The specific aims are: 1) To define role of B7 in T cell activation by the cutaneous immune system by characterizing B7 transcripts in keratinocytes and Langerhans cells, and examining the capacity of keratinocytes and Langerhans cells derived from a B7 deficient mouse strain to activate T cells. (2)To determine whether keratinocytes from the B7 deficient mouse strain have an additional B7-like ligand, termed Bx, and if so, clone and characterize this B7-like molecule We will determine whether keratinocytes from the B7 deficient mouse strain bind CTLA4Ig or CD28Ig and clone the gene for Bx using an expression cloning strategy.
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