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

Pedros, Christophe; Zhang, Yaoyang; Hu, Joyce; Choi, Youn Soo; Canonigo-Balancio, Ann J.; Yates, John R.; Altman, Amnon; Crotty, Shane; Kong, Kok Fai

doi:10.1038/ni.3463

Cited by 59 publications

(71 citation statements)

References 55 publications

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“…S1E, as previously described (Zheng et al, 2009). Nevertheless, given the moderate effect on Tfh differentiation by shRNA-mediated knockdown of ICOS expression (Pedros et al, 2016), it is unlikely to fully explain the marked Tfh defect of Irf4 −/− cells. Thus, besides T cell activation, Irf4 likely plays an essential role in regulating the differentiation of Tfh cells.…”

Section: Resultsmentioning

confidence: 99%

The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate

et al. 2017

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Summary Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses towards antibody production via Tfh cells or inflammation by Teff cells. Tfh–Teff fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6–Blimp-1 counter-antagonism. We found that the TCR-signal induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh fate trajectories towards those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment towards low affinity binding sites within Teff cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the “reader” of TCR signal strength, in turn, concentration-dependent activity of Irf4 “writes” T helper fate choice.

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Section: Resultsmentioning

confidence: 99%

The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate

et al. 2017

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“…The potent activation of Akt may explain, in part, the enhanced T cell persistence of ICOS-based CAR T cells, as Akt is a known T cell survival factor. Although PI3K is the main signaling molecule that is known to interact with ICOS, it has been recently reported that the cytoplasmic tail of ICOS has 2 potentially novel evolutionary conserved motifs (49). The ICOS proximal motif is homologous to a conserved motif found in the TNFR-associated factors TRAF2 and TRAF3, and it binds to the kinase TBK1 (49).…”

Section: Discussionmentioning

confidence: 99%

“…Although PI3K is the main signaling molecule that is known to interact with ICOS, it has been recently reported that the cytoplasmic tail of ICOS has 2 potentially novel evolutionary conserved motifs (49). The ICOS proximal motif is homologous to a conserved motif found in the TNFR-associated factors TRAF2 and TRAF3, and it binds to the kinase TBK1 (49). How these ICOS-specific motifs contribute to the observed phenotype of ICOS-based CAR T cells is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

Guedan¹,

Posey²,

Shaw³

et al. 2018

JCI Insight

412

364

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“…Other than known PI3K binding motif Tyr-x-x-Met (YxxM, where ‘x’ indicates any amino acid) of ICOS, Pedros et al using SILAC (stable isotope labeling) approach showed that ICOS cytoplasmic tail has other two conserved motifs, one Proximal SSSVHDPNGE (IProx) and second AVNTAKK motif. Retroviral transduction of CD4 + T cells (TCR transgenic for LCMV peptide gp 61–80) with ICOS mutant in PI3k-binding site of IProx motif and adoptive transfer into ICOS −/− mice and then LCMV infection fail to generate Tfh cells illustrating that IProx plays a critical positive role in Tfh differentiation (73). Importantly, IProx motif has homology with the conserved sequences with TRAF2 and TRAF3.…”

Section: Cytokine As Positive and Negative Regulators Of Tfh Differenmentioning

confidence: 99%

Regulators of Tfh Cell Differentiation

2016

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The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4+ T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule-associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155. On the other hand, Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7), surface receptor (PD-1, CTLA-4), transcription factors B lymphocyte maturation protein 1, signal transducer and activator of transcription 5, T-bet, KLF-2 signaling, and repressor miR 146a. Interestingly, miR-17–92 and FOXO1 act as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review, we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin ligase, and microRNA as positive and negative regulators for Tfh differentiation.

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

Cited by 59 publications

References 55 publications

The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate

The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate

Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

Regulators of Tfh Cell Differentiation

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