Lymphotoxin Beta Receptor in Intestinal Inflammation

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DESCRIPTION (provided by applicant): The mucosal immune system is a complex network of lymphoid compartments that function to protect the host from invading pathogens. However, these immune responses must be tightly controlled, as inappropriate immune responses can damage the mucosa, and adversely impact intestinal function. In this proposal we will investigate the function and genesis of isolated lymphoid follicles (ILFs), a recently appreciated member of the mucosal immune system. ILFs are organized lymphoid structures in the small intestine resembling Peyer's patches (PP), and possessing a follicle associated epithelium (FAE). The organized structure and cellular composition of ILFs suggests that ILFs facilitate effective interactions of antigen, antigen presenting cells, and lymphocytes. We have recently demonstrated that ILFs are unique amongst the mucosal organized lymphoid compartments in that their formation can be induced by lumenal stimuli. Therefore, ILFs represent an inducible reservoir of immune inductive sites, which could be manipulated to shape immune responses in a therapeutic manner. In the first specific aim we will examine the cellular populations within ILFs and examine the phenotype of immune responses mediated by these ILF cellular populations. We will accomplish these goals by isolating cellular populations from ILFs and examining the expression of cell surface markers that delineate functional lymphocyte and dendritic cell subsets. We will examine the cytokine production by isolated ILF cellular subpopulations in response to activating stimuli, and we will examine the ability of ILF dendritic cell populations to drive the differentiation of T-lymphocytes subsets. In the second specific aim we will examine the stage of ILF formation in which lymphotoxin sufficient Blymphocytes are required, the role of antigen experienced B-lymphocytes in ILF formation, and the role of CCR6 in ILF formation. To accomplish these goals we will examine ILF formation in B-cell receptor transgenic mice in the absence of exogenous antigen. We will examine ILF formation in bone marrow chimeric mice selectively reconstituted with lymphotoxin sufficient or deficient B-lymphocytes. We will examine ILF formation in CCR6 deficient mice, and in bone marrow chimeric mice selectively reconstituted with CCR6 sufficient cellular subpopulations. Long-term objectives of this proposal are to define pathways which will allow manipulation of ILF formation in a therapeutic manner.