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Nat Immunol. 2016 Jul;17(7):825-33. doi: 10.1038/ni.3463. Epub 2016 May 2.

A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1.

Author information

1
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
2
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
3
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
4
Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, California, USA.

Abstract

Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (TFH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) TFH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of TFH cells. These results reveal a previously unknown ICOS-TBK1 signaling pathway that specifies the commitment of GC TFH cells.

PMID:
27135603
PMCID:
PMC4915981
DOI:
10.1038/ni.3463
[Indexed for MEDLINE]
Free PMC Article

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