Abstract
We have examined the role of heparan sulphate in lymphocyte development and activation in mice by conditionally deleting the genes encoding the heparan sulphate biosynthetic enzymes N-deacetylase/N-sulphotransferase-1 and -2 (Ndst1 and Ndst2) and glucuronic acid/N-acetylglucosamine co-polymerase-1 (Ext1) in T cells and B cells, respectively. Ndst1 and Ndst2 are the only Ndst isoforms in T cells. In T-cell Ndst-deficient mice there were normal ratios of CD4(+)/CD8(+) cells in the blood, spleen and thymus, indicating no dramatic effect on development. However, Ndst-deficient T cells were hyperresponsive to low-level activation, suggesting that cell surface heparan sulphate plays a role in T-cell proliferation. The hyperresponsive state correlated with a decrease in cell surface heparan sulphate that occurs in response to activation in wild-type cells. There was a slight change in the number of developing B cells in B-cell Ext1-deficient mice, but the alteration did not cause a change in antibody production. These findings demonstrate that cell surface heparan sulphate may not play a crucial role in lymphocyte development, but can modulate the sensitivity of T cells to activation.