An investigation of the regulation of Sialoadhesin ligands on CD4+ T cells and its potential significance in Systemic Lupus Erythematosus

Abstract

Sialoadhesin (Sn) is the prototype of Sialic acid binding Immunoglobulin-Like Lectins(SIGLECs). Sn is expressed on macrophages from metalophilic zone and subcapsular sinus in spleen and lymph nodes respectively. Under inflammatory conditions, Sn expression is upregulated on macrophages. Sn was recently found to downregulate CD4+Foxp3+ regulatory T cells (Tregs) in a mouse model of experimental autoimmune Encephalomyelitis (EAE); however the nature of the interaction between Sn and CD4+ T cells is not well characterised. The first aim of this thesis was to investigate the upregulation of Sn ligand (SnL) on CD4+ T cells in vitro. Both Tregs and CD4+Foxp3-T cells upregulate SnL following T cell receptor (TCR) ligation. SnL+CD4+ T cells express a higher state of activation and proliferation compared to SnL- counterparts. Furthermore, engaging SnL on activated CD4+ T cells induces cell death. Experiments performed to analyse the nature of sialylation changes and expression of glycosyltransferases on SnL+ CD4+ T cells, indicated that terminal sialic acids on Nlinked glycans represent a putative ligand for Sn.The second aim of this project was to analyse the role of Sn in a mouse model of systemic lupus erythematosus (SLE). NZB x NZW F1 (BWF1) hybrid model was used for this purpose. Examination of Sn expression on pre-diseased and diseased mice showed that Sn expression is upregulated around the disease onset and went down to pre-disease levels subsequently. This finding might suggest a role for Sn in enhancing cell death and downregulating Treg and therefore augmenting immune dysregulation. Two approaches were used to further study the role of Sn in this model. First, Sn neutralising antibodies were used prophylactically to study the effect on disease severity. Secondly, using speed congenic method, BWF1 mice deficient for Sn were generated. Data presented in this thesis suggest that Sn might play an antiinflammatory role in murine SLE.EThOS - Electronic Theses Online ServiceWellcome TrustGBUnited Kingdo