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dc.contributor.authorBandala-Sanchez, Estheren_US
dc.contributor.authorBediaga, Naiaraen_US
dc.contributor.authorGoddard-Borger, Ethanen_US
dc.contributor.authorNgui, Katrinaen_US
dc.contributor.authorNaselli, Gaetanoen_US
dc.contributor.authorStone, Natalieen_US
dc.contributor.authorNeale, Alanaen_US
dc.contributor.authorPearce, Lesleyen_US
dc.contributor.authorWardak, Ahmaden_US
dc.contributor.authorCzabotar, Peteren_US
dc.contributor.authorHaselhorst, Thomasen_US
dc.contributor.authorMaggioni, Andreaen_US
dc.contributor.authorHartley-Tassell, Laurenen_US
dc.contributor.authorAdams, Timothyen_US
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.en_US
dc.publisherNational Academy of Sciencesen_US
dc.publisher.placeUnited Statesen_US
dc.relation.ispartofjournalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.fieldofresearchBiochemistry and Cell Biology not elsewhere classifieden_US
dc.titleCD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell functionen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dc.type.codeC - Journal Articlesen_US
gro.hasfulltextNo Full Text

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