T lymphocytes are a major component of the inflammatory response and aberrant regulation of T cell activation and differentiation may be central to the pathogenesis of asthma. The CD28 co-stimulatory receptor is a critical regulator of T cell activation and differentiation, and thus may be an important target for therapy of immune mediated diseases. Manipulation of this receptor has been shown to alter the course of several animal models of disease, inducing models of antigen-induced airway inflammation. Accordingly, the primary goal of this proposal is to increase our understanding of the cellular and molecular basis by which CD28 modulates the T cell response to antigen. CD28 regulates multiple aspects of T cell functions, including proliferation, adhesion, T helper cell phenotype development and cell survival. The PI demonstrates that CD28 is essential for the development of antigen-induced inflammation in a murine model of airway disease. Sensitized CD28-deficient mice fail to develop airway inflammation or eosinophilia in response to antigen challenge. Examination of T helper cell phenotype in CD28 -/- mice demonstrates a defect in Th2 cytokine gene expression. The mechanism by which CD28 regulates these diverse aspects of T cell function is poorly understood, but likely involves multiple signaling pathways. Studies in transformed cell lines have implicated specific domains in the cytoplasmic trail of CD28 as important in signaling, but no consensus exists as to what is required for CD28 function in primary cells or in vivo responses. The data in primary T cells demonstrates a requirement for specific proline mediated interactions with the non-receptor tyrosine kinase lck in the regulation of T cell proliferation by CD28. The PI hypothesizes that multiple distinct structural domains of CD28 modulate specific features of T cell activation and differentiation. To address this, the following specific aims have been proposed: 1) determine the structural features of CD28 required for co-stimulation of primary T cells in vitro; and 2) characterize the specific cellular and molecular determinants by which CD28 regulates airway inflammation in vivo. These studies will provide critical data as to the regulation of T cell directed immune responses, and provide a rational basis for the development of new therapeutic strategies in the treatment of inflammatory lung disease.
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