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A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells

Follicular helper T (T(FH)) cells and follicular regulatory T (T(FR)) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathway...

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Autores principales: Leavenworth, Jianmei W., Verbinnen, Bert, Yin, Jie, Huang, Huicong, Cantor, Harvey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405167/
https://www.ncbi.nlm.nih.gov/pubmed/25436971
http://dx.doi.org/10.1038/ni.3050
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author Leavenworth, Jianmei W.
Verbinnen, Bert
Yin, Jie
Huang, Huicong
Cantor, Harvey
author_facet Leavenworth, Jianmei W.
Verbinnen, Bert
Yin, Jie
Huang, Huicong
Cantor, Harvey
author_sort Leavenworth, Jianmei W.
collection PubMed
description Follicular helper T (T(FH)) cells and follicular regulatory T (T(FR)) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that ICOS activation in CD4(+) T cells promotes the interaction of the p85α regulatory subunit of the signaling kinase PI3K and intracellular osteopontin (OPN-i), followed by nuclear translocation of OPN-i, interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 expression by OPN-i is essential for sustained T(FH) and T(FR) cell responses and regulation of the germinal center B cell response to antigen. As such, the p85α–OPN-i axis represents a molecular bridge that couples ICOS activation to Bcl-6-dependent functional differentiation of T(FH) and T(FR) cells and suggests new therapeutic avenues to manipulate their responses.
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spelling pubmed-44051672015-07-01 A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells Leavenworth, Jianmei W. Verbinnen, Bert Yin, Jie Huang, Huicong Cantor, Harvey Nat Immunol Article Follicular helper T (T(FH)) cells and follicular regulatory T (T(FR)) cells regulate the quantity and quality of humoral immunity. Although both cell types highly express the co-stimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that ICOS activation in CD4(+) T cells promotes the interaction of the p85α regulatory subunit of the signaling kinase PI3K and intracellular osteopontin (OPN-i), followed by nuclear translocation of OPN-i, interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 expression by OPN-i is essential for sustained T(FH) and T(FR) cell responses and regulation of the germinal center B cell response to antigen. As such, the p85α–OPN-i axis represents a molecular bridge that couples ICOS activation to Bcl-6-dependent functional differentiation of T(FH) and T(FR) cells and suggests new therapeutic avenues to manipulate their responses. 2014-12-01 2015-01 /pmc/articles/PMC4405167/ /pubmed/25436971 http://dx.doi.org/10.1038/ni.3050 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Leavenworth, Jianmei W.
Verbinnen, Bert
Yin, Jie
Huang, Huicong
Cantor, Harvey
A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title_full A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title_fullStr A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title_full_unstemmed A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title_short A p85α–osteopontin axis couples the ICOS receptor to sustained Bcl-6 expression by follicular helper and regulatory T cells
title_sort p85α–osteopontin axis couples the icos receptor to sustained bcl-6 expression by follicular helper and regulatory t cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405167/
https://www.ncbi.nlm.nih.gov/pubmed/25436971
http://dx.doi.org/10.1038/ni.3050
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