THE T-CELL RESPONSE TO ANTIGEN

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A gene product that may play an early and critical role in these responses is a T-cell cytokine we have cloned termed Eta-1 (for Early T-lymphocyte activation-1). This gene has the following features: the Eta-1 gene is the most abundant newly-transcribed mRNA species expressed after TCR ligation, encoding a secreted phosphoprotein that leads to macrophage activation and chemotactic migration in vitro and in vivo and may account for genetic resistance to several intracellular pathogens. Overexpression of Eta-1 may play a central role in the pathogenesis of autoimmune disease in MRL/lpr mice. Our recent studies indicate that mice deficient in Eta-1 gene expression secondary to targeted gene mutation fail to develop DTH responses and associated Th1-driven autoimmunity after viral infection. These defective immune responses are associated with diminished in vivo production of IL-12 and excessive production of IL-10. This in vivo response may reflect an interaction between the N- terminal portion of Eta-1 and its integrin receptor, alphavbeta3, leading to IL-12 secretion and inhibition of IL-10 expression. These findings identify Eta-1 as a critical and non-redundant cytokine that initiates Th1 inflammatory responses and provide a mechanism by which T-cell recognition of foreign antigens may govern the development of antimicrobial inflammatory responses. We propose structure/function studies to define the molecular interaction between Eta-1 and macrophage receptor(s) (SA1) and subsequent intracellular events (SA2) that regulate IL-12/IL-10 gene expression. We also propose studies to define the role of Eta-1 in Th1/DTH development to conventional antigen (SA3) and its contribution to Th1-dependent responses to microbiological pathogens and organ-specific autoimmune disease (SA4).