Activation of regulatory T cells triggers specific changes in glycosylation associated with Siglec-1-dependent inflammatory responses

Wellcome Open Research

article

Gang Wu¹  Gavuthami Murugesan¹  Manjula Nagala¹  Alex McCraw¹  Stuart M. Haslam²  Anne Dell²  Paul R. Crocker¹ 

[1] Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee;Department of Life Sciences, Imperial College London

关键词: Regulatory T cell;    macrophage;    inflammation;    sialic acid;    glycomics;    proteomics;   

DOI  :  10.12688/wellcomeopenres.16834.1

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Siglec-1 is a macrophage lectin-like receptor that mediates sialic acid-dependent cellular interactions. Its upregulation on macrophages in autoimmune disease was shown previously to promote inflammation through suppressing the expansion of regulatory T cells (Tregs). Here we investigate the molecular basis for Siglec-1 binding to Tregs usingin vitro-induced cells as a model system.Methods: Glycosylation changes that affect Siglec‑1 binding were studied by comparing activated and resting Tregs using RNA-Seq, glycomics, proteomics and binding of selected antibodies and lectins. A proximity labelling and proteomics strategy was used to identify Siglec-1 counter-receptors expressed on activated Tregs.Results: Siglec-1 binding was strongly upregulated on activated Tregs, but lost under resting conditions. Glycomics revealed changes in N-glycans and glycolipids following Treg activation and we observed changes in expression of multiple ‘glycogenes’ that could lead to the observed increase in Siglec-1 binding. Proximity labelling of intact, living cells identified 49 glycoproteins expressed by activated Tregs that may function as Siglec-1 counter-receptors. These represent ~5% of the total membrane protein pool and were mainly related to T cell activation and proliferation. We demonstrate that several of these counter-receptors were upregulated following activation of Tregs and provide initial evidence that their altered glycosylation may also be important for Siglec-1 binding.Conclusions: We provide the first comprehensive analysis of glycan changes that occur in activated Tregs, leading to recognition by the macrophage lectin, Siglec-1 and suppression of Treg expansion. We furthermore provide insights into glycoprotein counter-receptors for Siglec-1 expressed by activated Tregs that are likely to be important for suppressing Treg expansion.

【 授权许可】

CC BY