DEVELOPMENT AND FUNCTION OF INTESTINAL T-LYMPHOCYTES

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The gastrointestinal tract is the portal of entry for many pathogens and toxins and serves as a significant site of infection in both healthy and immunocompromised hosts. An elaborate specific immune system consisting of both humoral and cellular components maintains the integrity of the small intestine against microbial invasion. However, much of the functional potential of the cellular arm of specific mucosal immunity is poorly understood. This proposal describes a research plan that uses experimental enteric reovirus infection in mice to expand our understanding of mucosal cellular immunity. The work will focus on an analysis of the effects of reovirus infection on the development of virus-specific intraepithelial lymphocytes (IEL). The developmental and functional relationship between IEL and other intestinal lymphocytes will also be explored by comparing the specificity of virus-specific cytotoxic IEL and other intestinal T-cells that appear following enteric reovirus infection. In addition, a comparison of the families of alpha/beta T-cell receptors for antigen (TCR) that are expressed on virus-specific IEL and other mucosal lymphocytes will be made using flow cytometric analyses. The in vivo functional activity of mucosal lymphocytes in the response to enteric reovirus infection will also be examined. The capacity of distinct populations of mucosal lymphocytes to proliferate in vivo following enteric challenge will be assessed by measuring in vivo incorporation of the thymidine analog 5-bromo-2'deoxyuridine. Cytokine and cytokine mRNA production by gut lymphocytes from enterically primed mice will also provide insight into the effector function of mucosal T-cells following virus infection. Finally, experiments are proposed to examine enteric immunity in mire which do not produce CD8+ alpha/beta TCR+ lymphocytes. This work will provide a better understanding of the role of CD8+ intestinal T-cells in the mucosa] immune response. The proposed work is important for understanding the pathogenesis of microbes that cause gastrointestinal disease such as rotavirus and enteropathogenic bacteria, as well as pathogens that cause systemic disease but gain entry through mucosal surfaces such as human immunodeficiency virus (HIV). In addition to being important for infectious diseases, this work has broad implications for developing treatments for systemic and local autoimmune diseases and cancer. It is likely that mucosal T-cells play a major role in controliing and/or exacerbating autoimmune diseases and cancer; yet little is known about the role of intestinal T-cells in these diseases. The proposed studies in this well characterized system will provide new, critical information about the role of T-cells in intestinal immunity.