Designing an improved T-cell mobilising CXCL10 mutant through enhanced GAG binding affinity. Issue 8 (23rd January 2020)

• Record Type: Journal Article
• Authors: Gerlza, Tanja; Nagele, Michael; Gschwandtner, Martha; Winkler, Sophie; Kungl, Andreas
• Is Part Of: Protein engineering, design & selection. Volume 32:Issue 8(2019)
• Page Start: 367
• Page End: 373
• Publication Date: 2020-01-23
• Subjects: chemokines -- CXCL10 -- glycosaminoglycan -- surface plasmon resonance -- T-cell immobiliser; Protein engineering -- Periodicals; 660.63
• DOI: 10.1093/protein/gzz043
• Languages: English
• ISSNs: 1741-0126

Abstract

Abstract: The chemokine CXCL10 is released by a plethora of cells, including immune and metastatic cancer cells, following stimulation with interferon-gamma. It acts via its GPC receptor on T-cells attracting them to various target tissues. Glycosaminoglycans (GAGs) are regarded as co-receptors of chemokines, which enable the establishment of a chemotactic gradient for target cell migration. We have engineered human CXCL10 towards improved T-cell mobilisation by implementing a single site-directed mutation N20K into the protein, which leads to a higher GAG binding affinity compared to the wild type. Interestingly, this mutation not only increased T-cell migration in a transendothelial migration assay, the mutant intensified T-cell chemotaxis also in a Boyden chamber set-up thereby indicating a strong role of T-cell-localised GAGs on leukocyte migration. A CXCL10 mutant with increased GAG-binding affinity could therefore potentially serve as a T-cell mobiliser in pathological conditions where the immune surveillance of the target tissue is impaired, as is the case for most solid tumors.