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TACI isoforms regulate ligand binding and receptor function

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dc.contributor.author García-Carmona, Yolanda
dc.contributor.author Ting, Adrian T.
dc.contributor.author Radigan, Lin
dc.contributor.author Athuluri Divakar, Sai Krishna
dc.contributor.author Chávez, Jose
dc.contributor.author Meffre, Eric
dc.contributor.author Cerutti, Andrea, 1965-
dc.contributor.author Cunningham-Rundles, Charlotte
dc.date.accessioned 2019-04-29T07:55:24Z
dc.date.available 2019-04-29T07:55:24Z
dc.date.issued 2018
dc.identifier.citation Garcia-Carmona Y, Ting AT, Radigan L, Athuluri Divakar SK, Chavez J, Meffre E. et al. TACI isoforms regulate ligand binding and receptor function. Front Immunol. 2018 Oct 2;9:2125. DOI: 10.3389/fimmu.2018.02125
dc.identifier.issn 1664-3224
dc.identifier.uri http://hdl.handle.net/10230/37142
dc.description.abstract TACI signals activate B cell proliferation, isotype switch and antibody production in both normal immunity and autoimmune states. In contrast to murine TACI, the human TACI gene undergoes alternative splicing to produce short and long isoforms (TACI-S and TACI-L). In previous studies, we showed that transduction of the short, but not long isoform, into murine B cells or human pre-B cells lacking TACI, caused them to become transcriptional and morphologically identical to plasma cells. These data suggest that the expression of different isoforms in humans provides unique controls on B cell maturation. In these studies we show that TACI-S and TACI-L form complexes in a ligand-independent manner, not dependent on a single extracellular domain. Both TACI isoforms are detectable in the endosomal cellular compartment where they co-localize with MyD88, TRAF6, and the activated 65 kDa form of TLR9, depending on a conserved intracellular TACI sequence. In contrast to TACI-L expressing cells, or cells bearing both isoforms, TACI-S binds ligands BAFF and APRIL with substantially greater affinity and promotes enhanced NF-kB activation. Using isoform-specific monoclonal antibodies, we show that while TACI-L is predominant as a surface receptor surface on human B cells, significantly more TACI-S is noted in the intracellular compartment and also in marginal zone, isotype switched and plasmablast in resting B cells. TACI-S is increased in tonsillar B cells and also in the intracellular compartment of activated peripheral B cells. These data shows that alternative splicing of the human TACI gene leads to two isoforms both of which intersect with MyD88 and TRAF6 and form complexes with TLR9, but the two isoforms have different ligand binding capacities, subcellular locations and activation capabilities.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Frontiers
dc.relation.ispartof Frontiers in Immunology. 2018 Oct 2;9:2125
dc.rights © 2018 Garcia-Carmona, Ting, Radigan, Athuluri Divakar, Chavez, Meffre, Cerutti and Cunningham-Rundles. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title TACI isoforms regulate ligand binding and receptor function
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3389/fimmu.2018.02125
dc.subject.keyword B cell
dc.subject.keyword TACI
dc.subject.keyword TLR9
dc.subject.keyword Activation
dc.subject.keyword Isoforms
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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