Although eosinophils can function as end-stage effector cells, eosinophils also possess capacities to mediate other immunologic functions, including newly recognized cooperative interactions with lymphocytes. Eosinophils, longer-lived than neutrophils, are predominantly tissue-dwelling cells normally localized in mucosal tissues which interface with the external environment. In addition, increased numbers of eosinophils are present in association with allergic and certain related immunologic responses. Eosinophils are subject to stimulatory effects of cytokines released by other cells and can be functionally activated on disease states. Activation can modulate not only effector functions of eosinophils but also newly identified capabilities of eosinophils to interact with and respond to lymphocytes. This proposal will focus on delineating the mechanisms and consequences of collaborative interactions that occur between human eosinophils and lymphocytes. First, the capacity of eosinophils to stimulate lymphocytes will be studied. These investigations will include studies of the roles of eosinophils as HLA-DR dependent, MHC- restricted antigen presenting cells, including the expression by eosinophils of requisite co-stimulatory (notably B7), and the capacities of eosinophils to process particulate antigens and to utilize various antibody classes to facilitate antigen processing. A lymphokine, lymphocyte chemoattractant factor, which acts on CD4+ lymphocytes and other CD4+ leukocytes, is newly recognized to be elaborated by eosinophils. The molecular structure of the eosinophil-derived cytokine, conditions eliciting its formation and release from eosinophils and its effects during eosinophil-lymphocyte interactions will be studied. The effects of other specific eosinophil-derived cytokines on lymphocyte functioning will be evaluated. Second, the activities of lymphocytes in modulating eosinophil functions will be studied. These will include studies of the actions of lymphocyte chemoattractant factor on eosinophils, which themselves express CD4, interleukin-2 on interleukin-2 receptor bearing eosinophils and a novel low molecular lymphokine. Third, the functions of specific alpha4 integrins expressed on eosinophils, alpha4beta1 and alpha4beta7, will be investigated to define their roles in mediating eosinophil activation and in regulating eosinophil-lymphocyte interactions. These studies aim to provide an understanding of the normal homeostatic functions of eosinophils as they are resident in submucosal sites and of the interactions of eosinophils with lymphocytes during acute and chronic allergic and inflammatory diseases.
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