Immune responses are tightly regulated to provide sufficient immunity to destroy pathogens, yet maintain control of effector populations so that autoimmunity or excessive inflammatory reactions, which might be harmful to the host, are avoided. IL-2 likely plays a significant role in this regulatory process, as it promotes either T cell death or survival depending on the physiologic state of the T cell. Preliminary data from this laboratory indicate that IL-2 is sequestered in lymphoid organs such as the spleen and thymus. Our studies also show that heparan sulfate-bound IL-2, so localized, promotes proliferation and primes cells for activation-induced cell death in vivo. These studies suggest that heparan sulfate may position IL-2 in lymphoid organs to help maintain T cell homeostasis. Using IL-2 deficient mice wherein the extracellular matrix is """"""""reconstituted"""""""" with exogenous IL-2, the studies that follow will attempt to determine the significance of heparan sulfate-bound IL-2 to immune function. This application will seek to ascertain: (1) whether immobilization of IL-2 by heparan sulfate alters the potency of IL-2 mediated responses; (2) whether heparan sulfate-bound IL-2 differentially localizes proliferation and apoptosis in vivo; and (3) the role of heparan sulfate-bound IL-2 in an in vivo model of immune-mediated colitis. These studies will help delineate how and to what extent heparan sulfate-bound IL-2 regulates T cell homeostasis, and will lead to a better understanding of how localization of IL-2, a cytokine of major import to immune function, is modulated in vivo.
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