Dataset Information

Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).

ABSTRACT: TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF-?B activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD137-induced NF-?B activation in cultured cells and in gene-transferred hepatocytes in vivo, while silencing these deubiquitinases enhanced CD137 costimulation of primary human CD8 T cells. Therefore A20 and CYLD directly downregulate the signaling from a T and NK-cell costimulatory receptor under exploitation for cancer immunotherapy in clinical trials.

SUBMITTER: Azpilikueta A

PROVIDER: S-EPMC5739564 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).

Azpilikueta Arantza A Bolaños Elixabet E Lang Valerie V Labiano Sara S Aznar Maria A MA Etxeberria Iñaki I Teijeira Alvaro A Rodriguez-Ruiz Maria E ME Perez-Gracia Jose L JL Jure-Kunkel Maria M Zapata Juan M JM Rodriguez Manuel S MS Melero Ignacio I

Oncoimmunology 20170921 1

TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF-κB activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD ...[more]

PMID: 29296520

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Project description:The activation of TLR-MyD88 (Toll like receptor- Myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2 stimulated and unstimulated T cell receptor transgenic âpmelâ and MyD88-/-pmel CD8+ T cells and identified changes in the expression levels of several TNF family members. In particular, TLR-stimulation increased 4-1BB levels in pmel but not in MyD88-/-pmel T cells. A link between 4-1BB and TLR1-TLR2 signaling in CD8+ T cells was highlighted by in fact that 4-1BB-/- T cells exhibited suboptimal responses to TLR1-TLR2 agonist, but responded normally to CD28 or OX40 costimulation. Moreover, blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1-TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1-TLR2âstimulated cells were not due to increased mRNA stability nor increased histone activation but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1-TLR2 ligand with an agonistic anti-4-1BB antibody enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. CD8+ T cells from the B6.Cg-Thy1/Cy Tg(TcraTcrb)8Rest/J mice, referred to as âpmelâ T cells or from MyD88 knockout pmel mice (MyD88â/âpmel) were sorted. pmel and MyD88â/âpmel T cells were activated using MyD88â/â CD8 T cell-depleted splenocytes pulsed with 10ng/ml of mgp100. This was with or without 10Âµg/ml of Pam3CSK4. pmel or MyD88â/âpmel CD8 T cells were enriched and used for the extraction of RNA used for genomic analysis.

Dataset Information

Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).

Publications

Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB).

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