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

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

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.

MeSH terms

  • Animals
  • Antibody Formation / genetics
  • B-Lymphocytes / physiology*
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Germinal Center / immunology*
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 3 / genetics

Substances

  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases