TY - JOUR
T1 - Directed evolution of a soluble human DR3 receptor for the inhibition of TL1A induced cytokine secretion
AU - Levin, Itay
AU - Zaretsky, Marianna
AU - Aharoni, Amir
N1 - Publisher Copyright:
© 2017 Levin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014949309&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0173460
DO - 10.1371/journal.pone.0173460
M3 - Article
C2 - 28278297
AN - SCOPUS:85014949309
SN - 1932-6203
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e0173460
ER -