Human intraepithelial lymphocytes (IEL), predominantly CD8+ T lymphocytes, migrate from the lamina propria to the epithelium where they reside at the basolateral aspect of epithelial cells (ECs). Here, they are capable of many types of cytotoxic activities that destroy infected or malignantly-transformed ECs. We hypothesize that abnormal EC produce chemokines that attract IELs which then lyse these abnormal ECs. The preliminary data show that IEL express a promiscuous IL-8 receptor that binds both alpha and beta chemokines, that IL-15 is more potent than any other known cytokine in inducing lymphokine-activated killer (LAK) activity, and that IL-10 and IL-12 both potentiate this activity. The first Specific Aim will examine the chemotactic response of IEL, in particular, the number and affinity of receptors of IL-8 and RANTES. The kinetics of receptor turnover and regulation will be addressed as well the mechanism of chemotaxis and chemokine secreted by ECs. The second Specific Aim will determine why IL-15 is a more potent inducer of LAK activity than IL-2 for IEL but not PBL. The number of cytokine receptors on each cell type will be determined by radioligand binding and immunofluorescence. The mechanism of action, whether mediated by perforin, Fas, or TNFalpha, the mechanism of IL-4 down- regulation of IL-15 induced LAK activity, and the potential arrest of IEL apoptosis by IL-15 will be involved. The third Specific Aim will determine how IL-10 and IL-12 increase IEL LAK activity. The phenotypes of the IEL expressing receptors for these cytokines will be determined as well as an assessment as to whether the cytokines enhanced cytotoxic activity of NK or non-NK cells. The unusual finding of IL-10 augmentation of IL-2- induced proliferation of IELs will be pursued further. These studies will determine the mechanism of IEL chemotaxis toward secreted products of ECs, why IL-15 is more potent than IL-2 in inducing LAK activity by IELs, and how IL-10 and IL-12 augment this activity.
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