Regulation of T Cell Deletion by Heparan Sulfate Bound Interleukin 2
lnterleukin-2 (IL-2), as evidenced by the lymphoproliferative disorders and autoimmunity observed in IL-2 deficient mice, plays a prominent role in both T cell proliferation and deletion. Therefore, the availability of this cytokine is tightly controlled. One mechanism altering the local availability of IL-2 is association with heparan sulfate, a glycosaminoglycan found on cell surfaces and within extracellular matrices. Because this interaction was established in vitro, to date, the implications of this interaction for normal immune function have not been investigated. We therefore asked how heparan sulfate-bound IL-2 might alter immune responses both in vitro and in vivo. Our findings demonstrate that the association between IL-2 and heparan sulfate localizes lL-2 to lymphoid organs such as the spleen and thymus, with minimal localization in lymph nodes. Heparan sulfate-bound TL-2 is also found in the glomeruli of the kidney, and along certain endothelial cell surfaces. In vitro, heparan sulfate-bound IL-2 promotes proliferation of an IL-2 dependent cell line. ln vivo, by "reconstituting" the extracellular matrices of IL-2 deficient mice with IL-2, heparan sulfate-bound lL-2 promotes antigen-specific T cell proliferation and activation-induced cell death. Activation-induced cell death is enhanced in both the spleen and the thymus. Because deletion in both the thymus and spleen (Lu, et al, Transplantation 68:747) may be important in acquired "tolerance" associated with the concomitant transplantation of solid organs and immature dendritic cells, heparan sulfate-bound IL-2 may contribute to this process by promoting apoptosis at these sites. Disruption of the interaction between IL-2 and heparan sulfate, perhaps through the administration of heparin or through the production of anti-heparan sulfate antibodies (seen in many autoimmune diseases), may therefore abrogate this pro-apoptotic influence.
Wrenshall, L. E.,
Miller, J. O.,
& Platt, J. L.
(2000). Regulation of T Cell Deletion by Heparan Sulfate Bound Interleukin 2. Transplantation, 69 (8), S380-S380.