Directed evolution of a soluble human DR3 receptor for the inhibition of TL1A induced cytokine secretion

Itay Levin, Marianna Zaretsky, Amir Aharoni

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

TNF-like 1A (TL1A) is a cytokine belonging to the TNF superfamily that promotes inflammation in autoimmune diseases. Inhibiting the interaction of TL1A with the endogenous deathdomain receptor 3 (DR3) offers a therapeutic approach for treating TL1A-induced autoimmune diseases. Here, we generated improved DR3 variants showing increased TL1A binding affinity and stability using a directed evolution approach. Given the high cysteine content and post-translational modification of DR3, we employed yeast surface display and expression in mammalian cell lines for screening, expression and characterization of improved DR3 variants. A cell-based assay performed with the human TF-1 cell line and CD4+ T cells showed that two improved DR3 mutants efficiently inhibited TL1A-induced cell death and secretion of IFN-κ, respectively. These DR3 mutants can be used as drug candidates for the treatment of inflammatory bowel diseases and for other autoimmune diseases, including rheumatic arthritis and asthma.

Original languageEnglish
Article numbere0173460
JournalPLoS ONE
Volume12
Issue number3
DOIs
StatePublished - 1 Mar 2017

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General

Fingerprint

Dive into the research topics of 'Directed evolution of a soluble human DR3 receptor for the inhibition of TL1A induced cytokine secretion'. Together they form a unique fingerprint.

Cite this