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dc.contributor.authorBandala-Sanchez, Esther
dc.contributor.authorBediaga, Naiara G
dc.contributor.authorGoddard-Borger, Ethan D
dc.contributor.authorNgui, Katrina
dc.contributor.authorNaselli, Gaetano
dc.contributor.authorStone, Natalie L
dc.contributor.authorNeale, Alana M
dc.contributor.authorPearce, Lesley A
dc.contributor.authorWardak, Ahmad
dc.contributor.authorCzabotar, Peter
dc.contributor.authorHaselhorst, Thomas
dc.contributor.authorMaggioni, Andrea
dc.contributor.authorHartley-Tassell, Lauren A
dc.contributor.authorAdams, Timothy E
dc.contributor.authorHarrison, Leonard C
dc.description.abstractCD52, 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 α-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.
dc.publisherNational Academy of Sciences
dc.publisher.placeUnited States
dc.relation.ispartofjournalProceedings of the National Academy of Sciences of the United States of America
dc.subject.fieldofresearchBiochemistry and Cell Biology not elsewhere classified
dc.titleCD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorHartley-Tassell, Lauren E.
gro.griffith.authorHaselhorst, Thomas E.
gro.griffith.authorMaggioni, Andrea

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