Small changes in lymphocyte development and activation in mice through tissue‐specific alteration of heparan sulphate

Abstract

SummaryWe 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.

Glycotranscriptome study reveals an enzymatic switch modulating glycosaminoglycan synthesis during B‐cell development and activation

“…This blockade was likely related to the endogenous synthesis of GAGs associated with membrane PGs, since a similar blockade could not be obtained by checking in vitro the pro-B to pre-B transition in the presence of exogenous heparin. Interestingly, a similar partial blockade at the pro-B/pre-B transition has recently been reported in mice with a B-cell-specific inactivation of the GlcA/GlcNAc co-polymerase-1 (EXT1), another enzyme of HS synthesis [33].…”

Disruption of heparan sulfate proteoglycan conformation perturbs B-cell maturation and APRIL-mediated plasma cell survival

“…In marked contrast to our findings, Garner et al recently reported that conditional inactivation of the HS polymerase exostin-1 at the pro B-cell stage does not significantly affect B-cell maturation and antigen-dependent differentiation. 46 However, unlike in our model where all B lymphocytes contain the mutant Glce, the Cre-mediated deletion of exostin-1 in the study of Garner was incomplete, ranging from 50% to 85%. As also debated by these authors, positive selection of cells that escaped HS deletion could thus explain the absence of a B-cell phenotype in these mice.…”

“…This might be explained by the reduced size of the mature naive B-cell pool, also because the peak responses on repeated antigenic stimulation were normal, but a contribution of altered activation of T cells or altered T-cell help to the observed reduced antigen-specific immune responses in vivo cannot be ruled out. 46,47 On the other hand, the apparent inability of Glce Ϫ/Ϫ mice to maintain TNP-specific IgM and IgG antibody levels, suggests that Glce may be especially important for the longevity of plasma cells, a notion that is supported by the reduced numbers of BM plasma cells in Glce-deficient animals, as well as by the fact that the serum Ig concentrations remained reduced despite repeated immunizations. Whereas retention of plasma cells in the BM depends on the expression of CXCR4 by plasma cells and its ligand CXCL12 by the stromal cells, 48 survival of plasma cells and plasmablasts in spleen and BM was recently shown to be critically dependent on BAFF/APRIL.…”

Heparan Sulfate Proteoglycans

“…Floxed allele: decreased chemokine transcytosis and presentation and neutrophil infiltration in Tie2Cre mice ; decreased allergen-induced airway hyperresponsiveness and inflammation because of reduction in recruitment of eosinophils, macrophages, neutrophils, and lymphocytes in Tie2Cre mice (Zuberi et al 2009); decreased pathological angiogenesis in Tie2Cre mice (Fuster et al 2007); decreased vascular VEGF-induced hyperpermeability (Xu et al 2010a); decreased vascular smooth muscle cell proliferation, vessel size, and vascular remodeling after arterial injury in SM22aCre mice (Adhikari et al 2010a); mild effect on T-cell response in Tie2Cre;Ndst2 2/2 mice (Garner et al 2008); defective lacrimal gland development and Fgf10-Fgfr2b complex formation and signaling in LeCre mice ; defective lobuloalveolar development in mammary gland (Crawford et al 2010).…”