CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function

Bandala-Sanchez, E; GBediaga N; Goddard-Borger, ED; Ngui, K; Naselli, G; Stone, NL; Neale, AM; Pearce, LA; Wardak, A; Czabotar, P; Haselhorst, T; Maggioni, A; Hartley-Tassell, LA; Adams, TE; Harrison, LC

Author(s): Bandala-Sanchez, E; GBediaga N; Goddard-Borger, ED; Ngui, K; Naselli, G; Stone, NL; Neale, AM; Pearce, LA; Wardak, A; Czabotar, P; Haselhorst, T; Maggioni, A; Hartley-Tassell, LA; Adams, TE; Harrison, LC;
Details: Publication Year 2018,Volume 115,Issue #30,Page 7783-7788
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Journal Article
Abstract: CD52, a glycophosphatidylinositol (GPI)-anchored glycoprotein, is released in a soluble form following T cell activation and binds to the Siglec (sialic acid-binding Ig-like lectin)-10 receptor on T cells to suppress their function. We show that binding of CD52-Fc to Siglec-10 and T cell suppression requires the damage-associated molecular pattern (DAMP) protein, high-mobility group box 1 (HMGB1). CD52-Fc bound specifically to the proinflammatory Box B domain of HMGB1, and this in turn promoted binding of the CD52 N-linked glycan, in alpha-2,3 sialic acid linkage with galactose, to Siglec-10. Suppression of T cell function was blocked by anti-HMGB1 antibody or the antiinflammatory Box A domain of HMGB1. CD52-Fc induced tyrosine phosphorylation of Siglec-10 and was recovered from T cells complexed with HMGB1 and Siglec-10 in association with SHP1 phosphatase and the T cell receptor (TCR). Thus, soluble CD52 exerts a concerted immunosuppressive effect by first sequestering HMGB1 to nullify its proinflammatory Box B, followed by binding to the inhibitory Siglec-10 receptor, triggering recruitment of SHP1 to the intracellular immunoreceptor tyrosine-based inhibitory motif of Siglec-10 and its interaction with the TCR. This mechanism may contribute to immune-inflammatory homeostasis in pathophysiologic states and underscores the potential of soluble CD52 as a therapeutic agent.
Publisher: NAS
Research Division(s): Population Health And Immunity; Chemical Biology; Structural Biology
PubMed ID: 29997173
Publisher's Version: https://doi.org/10.1073/pnas.1722056115
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.1722056115
NHMRC Grants: NHMRC/1037321, NHMRC/1080887,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-07-23 09:32:16

Last Modified: 2018-09-21 08:56:29