Expression Cloning of the STRL33/BONZO/TYMSTR Ligand Reveals Elements of CC, CXC, and CX3C Chemokines

Abstract

STRL33/BONZO/TYMSTR is an orphan chemokine and HIV/SIV coreceptor receptor that is expressed on activated T lymphocytes. We describe an expression cloning strategy whereby we isolated a novel chemokine, which we name CXCL16. CXCL16 is an α (CXC) chemokine but also has characteristics of CC chemokines and a structure similar to fractalkine (neurotactin) in having a transmembrane region and a chemokine domain suspended by a mucin-like stalk. A recombinant version of CXCL16 fails to mediate chemotaxis to all known chemokine receptor transfectants tested but does mediate robust chemotaxis, high affinity binding, and calcium mobilization to Bonzo receptor transfectants, indicating that this is a unique receptor ligand interaction. In vitro polarized T cell subsets including Th1, Th2, and Tr1 cells express functional Bonzo, suggesting expression of this receptor in chronic inflammation, which we further verified by demonstration of CXCL16-mediated migration of tonsil-derived CD4+ T lymphocytes. CXCL16 is expressed on the surface of APCs including subsets of CD19+ B cells and CD14+ monocyte/macrophages, and functional CXCL16 is also shed from macrophages. The combination of unique structural features of both Bonzo and CXCL16 suggest that this interaction may represent a new class of ligands for this receptor family. Additionally, this chemokine might play a unique dual role of attracting activated lymphocyte subsets during inflammation as well as facilitating immune responses via cell-cell contact.

Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans

“…CXCL16, the chemokine and ligand for CXCR6, is highly expressed in lung, and the receptor and ligand may be involved in chronic inflammation. 11 Since we did not see any difference in susceptibility to PCP by CXCR6 genotype, our study suggests that the mechanism for developing PCP is different from the mechanism required for recovering from PCP. Susceptibility to PCP may be the result of a low T-cell count, while recovery from PCP may depend on recruiting T cells to the site of infection.…”

“…8 Additionally, the chemokine and ligand for CXCR6, CXCL16 is highly expressed in lung and chemotactic to CD4 + T cells. 11 Furthermore, CXCR6+ T cells are prevalent in tissue sites of inflammation and preferentially expressed by Th1 cells, making it a candidate gene for OIs and malignancies. 12 Since clinical AIDS is a composite of OIs and malignancies, it is not clear if genetic variants associated with receptors and chemokines control progression to AIDS or time to a specific OI or malignancy.…”

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…Although typically produced as soluble, secreted proteins, the chemokine CXCL16 also exists as a membrane-bound form, consisting of a chemokine domain, a mucin-type stalk, a single-pass transmembrane (TM) domain and a cytoplasmic tail [2,3]. The mucin stalks serve to tether the chemokines to the cell membrane, while soluble versions of CXCL16 can be released by the action of membrane metalloproteinases [4,5].…”

“…CXCL16 is expressed by APC, including subsets of CD14 + monocytes/macrophages and CD19 + B cells [3], and has a variety of functions. Membrane-bound, it serves as a scavenger receptor for phosphatidylserine and oxidised low-density lipoprotein [6], and facilitates the phagocytosis of bacteria [7].…”

“…Membrane-bound CXCL16 also facilitates the firm adhesion of cells expressing the G protein-coupled receptor CXCR6, such as activated T cells and NKT cells [10]. As a soluble chemokine, CXCL16 promotes chemotaxis via CXCR6, and serves as a chemoattractant for CXCR6 + T cells [2,3].…”