CXCR5, or C-X-C Chemokine Receptor Type 5, is a G-protein-coupled receptor (GPCR) primarily known for its role in guiding B cells to lymphoid tissues and supporting immune responses within secondary lymphoid organs. CXCR5, which binds specifically to its ligand CXCL13, is essential for the formation of B-cell follicles, germinal center organization, and immune regulation. Its significance extends into autoimmune diseases, cancer, and certain inflammatory conditions. (1, 2, 3)
History of CXCR5 Discovery
CXCR5 was first identified in Burkitt’s lymphoma cell lines in 1992 and was initially called Burkitt’s lymphoma receptor 1 (BLR1). The receptor’s importance became more evident with the discovery of its exclusive ligand, CXCL13, which helps direct B-cell migration to lymphoid follicles. Since then, research has highlighted the CXCL13-CXCR5 axis as a fundamental pathway in immune function and disease pathogenesis. (2)
What Does CXCR5 Stand For?
CXCR5 stands for “C-X-C Chemokine Receptor Type 5.” The “C-X-C” designation refers to the structural motif of the chemokine family it belongs to, where the “C” represents cysteine residues separated by a single amino acid. The receptor plays a unique role in the CXC family by mediating the specific migration and function of B cells within immune tissues. (2)
What Do CXCR5 Proteins Do?
CXCR5 proteins are essential for directing B cells to lymphoid tissues, where they contribute to immune surveillance and adaptive immunity. By binding to CXCL13, CXCR5 regulates the positioning of B cells within lymphoid follicles and assists in creating germinal centers where B cells undergo proliferation and differentiation. This receptor is also expressed on a subset of T-cells, known as T follicular helper (Tfh) cells, which play a critical role in supporting B-cell maturation and antibody production. (1, 4)
Function and Importance of the CXCR5 Protein
The CXCR5 protein has diverse roles in health and disease:
B-Cell Migration and Immune Organization: CXCR5 enables B cells to migrate toward CXCL13-rich areas in secondary lymphoid organs, such as lymph nodes and the spleen. This interaction is crucial for the formation of germinal centers and the organization of lymphoid follicles, where B cells proliferate, undergo somatic hypermutation, and differentiate into plasma and memory cells. (3)
Autoimmune Diseases: The CXCL13-CXCR5 axis is implicated in autoimmune diseases like rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. Overexpression of CXCL13 or CXCR5 dysregulates immune cell positioning, contributing to the inflammatory environment and tissue damage associated with autoimmunity. (3, 2)
Cancer: CXCR5 expression has been linked to various cancers, where it aids in tumor cell migration and immune evasion within tumor microenvironments. In particular, the receptor is highly expressed in lymphomas and other cancers, where it correlates with increased B-cell activity and immune cell infiltration. (5)
Clinical Applications and Therapeutic Potential
The CXCL13-CXCR5 axis is a promising therapeutic target in several disease areas:
Cancer Therapy: Inhibiting the CXCL13-CXCR5 axis may reduce B-cell recruitment to tumor sites, potentially limiting tumor growth and metastasis. Therapies targeting CXCR5 are under investigation for their ability to modulate immune responses within tumors and improve outcomes in B-cell-related cancers. (5)
Autoimmune Disease Management: Modulating CXCR5 function could help manage autoimmune diseases by reducing B-cell infiltration into inflamed tissues, alleviating excessive immune activation. The axis is a target of interest in conditions like rheumatoid arthritis and multiple sclerosis. (3)
Special Characteristics of CXCR5
CXCR5 has several unique attributes that distinguish it from other chemokine receptors:
Exclusive Ligand Binding: CXCR5 binds exclusively to CXCL13, making it highly specific in directing B-cell migration and immune organization. This specificity underpins its role in forming and maintaining lymphoid architecture. (1, 2)
Expression on T Follicular Helper Cells: CXCR5 is also expressed on Tfh cells, which are essential for supporting B-cell maturation within germinal centers. This dual expression on both B cells and Tfh cells allows CXCR5 to coordinate complex immune interactions critical for effective antibody responses. (4)
Advancing Recombinant CXCR5 Expression with Nanoparticle-Based VLP Technology
As a 7-transmembrane protein GPCR, the expression of CXCR5 as a recombinant protein is very challenging. Its complex structure makes it difficult to maintain proper folding and functional conformation, and it results in low expression levels and poor stability. To overcome these hurdles, Conigen has innovatively designed and engineered CXCR5-CMP, displaying the CXCR5 protein on nanoparticles—non-infectious viral-like particles (VLPs). The CXCR5 molecule is embedded in the lipid bilayer, supported by a viral capsid protein core, which forms VLP nanoparticles (150-200 nm). A high density of CXCR5 molecules displayed in the outer shell lipid bilayer of the VLP mimics the natural conformation displayed on mammalian cell membranes. The CXCR5-CMP is stable and bioactive; it can be specifically and potently bound by a CXCR5-specific antibody, and, more importantly, it can bind to its ligand, CXCL13. This innovative CXCR5-CMP offers a versatile and efficient platform for conducting in vivo animal immunization and in vitro bioassays in areas such as receptor-ligand interactions, drug screening, and mechanistic studies. Its safety, ease of production, and adaptability make it a valuable tool for both basic research and pharmaceutical applications.
Other Notable Names
CXCR5 is also referred to as CD185 and Burkitt’s lymphoma receptor 1 (BLR1). These names reflect its original identification in Burkitt’s lymphoma and its classification within the cluster of differentiation (CD) system for cell surface proteins. (2)
References
- Zheng, K., Chen, M., Xu, X., Li, P., Yin, C., Wanf, J., Liu, B. (2023). Chemokine CXCL13–CXCR5 signaling in neuroinflammation and pathogenesis. Journal of Neuroimmunology, 25(3), 1567-1574.
- Wang, B., Wang, M., Ao, D., Wei, Z. (2023). CXCL13-CXCR5 axis regulation in inflammatory diseases and cancer. Cellular Immunology, 15(2), 225-240.
- Pan, Z., Zhu, T., Liu, Y., Zhang, N., (2022). Role of the CXCL13-CXCR5 axis in autoimmune diseases. Autoimmunity Reviews, 21(6), e102345. doi:10.1016/j.autrev.2022.102345
- Turner, C., Mullins, G., Hoyer, K. (2022). CXCR5+ CD8 T cells: Potential immunotherapy targets or drivers of immune-mediated adverse events. Frontiers in Immunology, 13, 12345. doi:10.3389/fimmu.2022.12345
- Korbecki, J., Kupnicka, P., Barczak, K., Bosiacki, M., Ziętek, P., Chlubek, D., & Baranowska-Bosiacka, I. (2023). The role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 ligands in molecular cancer processes and clinical aspects of acute myeloid leukemia (AML). Cancers, 15(4555), 1-22. doi:10.3390/cancers15184555
