CXCR5 explained

C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 (cluster of differentiation 185) or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 (also known as BLC) and belongs to the CXC chemokine receptor family. It enables T cells to migrate to lymph node and the B cell zones. In humans, the CXC-R5 protein is encoded by the CXCR5 gene.^[1]

Tissue distribution and function

The BLR1 / CXCR5 gene is specifically expressed in Burkitt's lymphoma and lymphatic tissues, such as follicles in lymph nodes as well as in spleen. The gene plays an essential role in B cell migration.^[2] Through CXCL13 secretions B cells are able to locate the lymph node.

Additionally, some recent studies have suggested that CXCL13, through CXCR5, is capable of recruiting hematopoietic precursor cells (CD3⁻ CD4⁺) which would cause the development of lymph nodes and Peyer's Patches.^{[3] [4]}

Other studies highlight the role of CXCR5 in T cells, as they are unable to access B cell follicles without CXCR5 expression.^{[5] [6]} This is a key step in the production of high affinity antibodies as B cells and T cells need to interact in order to activate the Ig class switch.

CXCR5 has been shown to be expressed on both CD4^[7] and CD8^[8] T cells, though it is often regarded as the defining marker for T Follicular Helper (Tfh) cells.^[9]

Role in cancer development

Recently, it was shown that CXCR5 overexpression in breast cancer patients highly correlates with lymph node metastases,^[10] and elevated CXCR5 expression may contribute to abnormal cell survival and migration in breast tumors that lack functional p53 protein.^[11] Minor allele of SNP rs630923, located in the area of CXCR5 gene promoter and associated with the risk of multiple sclerosis, is responsible for appearance of MEF2C-binding site resulted in reduced CXCR5 gene promoter activity in B-cells during activation, that could lead to decreased autoimmune response ^[12]

While chemokines and chemokine receptors have been thought to be involved in cancer development and maintenance, recently CXCR5 has come under investigation for its role in metastatic progression of prostate cancer. A recent study has indicated that prostate cancer tissue as well as cell lines express higher non-basal levels of CXCR5.^[13] Furthermore, the study found a correlation between the level of CXCR5 and Gleason score. CXCR5 location was additionally considered and higher Gleason scores correlated with nuclear CXCR5 while cytoplasmic and membrane CXCR5 correlated with benign and early prostate cancers.

References

Further reading

• Lipp M, Müller G . Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking . Verhandlungen der Deutschen Gesellschaft Fur Pathologie . 87 . 90–101 . 2006 . 16888899 .
• Barella L, Loetscher M, Tobler A, Baggiolini M, Moser B . Sequence variation of a novel heptahelical leucocyte receptor through alternative transcript formation . The Biochemical Journal . 309 . Pt 3 . 773–779 . August 1995 . 7639692 . 1135699 . 10.1042/bj3090773 .
• Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B . B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5 . The Journal of Experimental Medicine . 187 . 4 . 655–660 . February 1998 . 9463416 . 2212150 . 10.1084/jem.187.4.655 .
• Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT . A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1 . Nature . 391 . 6669 . 799–803 . February 1998 . 9486651 . 10.1038/35876 . 4373691 . 1998Natur.391..799G .
• Müller G, Lipp M . Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules . Biological Chemistry . 382 . 9 . 1387–1397 . September 2001 . 11688722 . 10.1515/BC.2001.171 . 21366051 .
• Schaerli P, Loetscher P, Moser B . Cutting edge: induction of follicular homing precedes effector Th cell development . Journal of Immunology . 167 . 11 . 6082–6086 . December 2001 . 11714765 . 10.4049/jimmunol.167.11.6082 . free .
• Kim CH, Johnston B, Butcher EC . Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity . Blood . 100 . 1 . 11–16 . July 2002 . 12070001 . 10.1182/blood-2001-12-0196 . 37076470 . free .
• Carlsen HS, Baekkevold ES, Johansen FE, Haraldsen G, Brandtzaeg P . B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue . Gut . 51 . 3 . 364–371 . September 2002 . 12171958 . 1773345 . 10.1136/gut.51.3.364 .
• Battle TE, Yen A . Ectopic expression of CXCR5/BLR1 accelerates retinoic acid- and vitamin D(3)-induced monocytic differentiation of U937 cells . Experimental Biology and Medicine . 227 . 9 . 753–762 . October 2002 . 12324654 . 10.1177/153537020222700906 . 26070911 .
• Lisignoli G, Toneguzzi S, Piacentini A, Cattini L, Lenti A, Tschon M, Cristino S, Grassi F, Facchini A . Human osteoblasts express functional CXC chemokine receptors 3 and 5: activation by their ligands, CXCL10 and CXCL13, significantly induces alkaline phosphatase and beta-N-acetylhexosaminidase release . Journal of Cellular Physiology . 194 . 1 . 71–79 . January 2003 . 12447991 . 10.1002/jcp.10188 . 8031523 .
• Chan CC, Shen D, Hackett JJ, Buggage RR, Tuaillon N . Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma . Ophthalmology . 110 . 2 . 421–426 . February 2003 . 12578791 . 10.1016/S0161-6420(02)01737-2 .
• Flynn G, Maru S, Loughlin J, Romero IA, Male D . Regulation of chemokine receptor expression in human microglia and astrocytes . Journal of Neuroimmunology . 136 . 1–2 . 84–93 . March 2003 . 12620646 . 10.1016/S0165-5728(03)00009-2 . 39725685 .
• Lisignoli G, Piacentini A, Toneguzzi S, Grassi F, Tschon M, Cristino S, Facchini A, Mariani E . Age-associated changes in functional response to CXCR3 and CXCR5 chemokine receptors in human osteoblasts . Biogerontology . 4 . 5 . 309–317 . 2004 . 14618028 . 10.1023/A:1026203502385 . 20511946 .
• Aust G, Sittig D, Becherer L, Anderegg U, Schütz A, Lamesch P, Schmücking E . The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases . European Journal of Endocrinology . 150 . 2 . 225–234 . February 2004 . 14763921 . 10.1530/eje.0.1500225 . free .
• Howard OM, Dong HF, Su SB, Caspi RR, Chen X, Plotz P, Oppenheim JJ . Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate . Blood . 105 . 11 . 4207–4214 . June 2005 . 15713799 . 1895027 . 10.1182/blood-2004-07-2697 .
• Steinmetz OM, Panzer U, Kneissler U, Harendza S, Lipp M, Helmchen U, Stahl RA . BCA-1/CXCL13 expression is associated with CXCR5-positive B-cell cluster formation in acute renal transplant rejection . Kidney International . 67 . 4 . 1616–1621 . April 2005 . 15780119 . 10.1111/j.1523-1755.2005.00244.x . free .
• Hu C, Xiong J, Zhang L, Huang B, Zhang Q, Li Q, Yang M, Wu Y, Wu Q, Shen Q, Gao Q, Zhang K, Sun Z, Liu J, Jin Y, Tan J . PEG10 activation by co-stimulation of CXCR5 and CCR7 essentially contributes to resistance to apoptosis in CD19+CD34+ B cells from patients with B cell lineage acute and chronic lymphocytic leukemia . Cellular & Molecular Immunology . 1 . 4 . 280–294 . August 2004 . 16225771 .

Notes and References

1. Dobner T, Wolf I, Emrich T, Lipp M . Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt's lymphoma . European Journal of Immunology . 22 . 11 . 2795–2799 . November 1992 . 1425907 . 10.1002/eji.1830221107 . 35096818 .
2. Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M . A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen . Cell . 87 . 6 . 1037–1047 . December 1996 . 8978608 . 10.1016/S0092-8674(00)81798-5 . 17558174 . free .
3. Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI . Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis . The Journal of Experimental Medicine . 193 . 5 . 621–630 . March 2001 . 11238592 . 2193398 . 10.1084/jem.193.5.621 .
4. Finke D, Acha-Orbea H, Mattis A, Lipp M, Kraehenbuhl J . CD4+CD3- cells induce Peyer's patch development: role of alpha4beta1 integrin activation by CXCR5 . Immunity . 17 . 3 . 363–373 . September 2002 . 12354388 . 10.1016/S1074-7613(02)00395-3 . free .
5. Junt T, Fink K, Förster R, Senn B, Lipp M, Muramatsu M, Zinkernagel RM, Ludewig B, Hengartner H . CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses . Journal of Immunology . 175 . 11 . 7109–7116 . December 2005 . 16301613 . 10.4049/jimmunol.175.11.7109 . free .
6. Hardtke S, Ohl L, Förster R . Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help . Blood . 106 . 6 . 1924–1931 . September 2005 . 15899919 . 10.1182/blood-2004-11-4494 . free .
7. Chevalier N, Jarrossay D, Ho E, Avery DT, Ma CS, Yu D, Sallusto F, Tangye SG, Mackay CR . CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses . Journal of Immunology . 186 . 10 . 5556–5568 . May 2011 . 21471443 . 10.4049/jimmunol.1002828 . free .
8. He R, Hou S, Liu C, Zhang A, Bai Q, Han M, Yang Y, Wei G, Shen T, Yang X, Xu L, Chen X, Hao Y, Wang P, Zhu C, Ou J, Liang H, Ni T, Zhang X, Zhou X, Deng K, Chen Y, Luo Y, Xu J, Qi H, Wu Y, Ye L . Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection . Nature . 537 . 7620 . 412–428 . August 2016 . 27501245 . 10.1038/nature19317 . 4469688 . 2016Natur.537..412H .
9. Moser B . CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells . Frontiers in Immunology . 6 . 296 . 2015 . 26106395 . 4459225 . 10.3389/fimmu.2015.00296 . free .
10. Biswas S, Sengupta S, Roy Chowdhury S, Jana S, Mandal G, Mandal PK, Saha N, Malhotra V, Gupta A, Kuprash DV, Bhattacharyya A . CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis . Breast Cancer Research and Treatment . 143 . 2 . 265–276 . January 2014 . 24337540 . 10.1007/s10549-013-2811-8 . 2937341 .
11. Mitkin NA, Hook CD, Schwartz AM, Biswas S, Kochetkov DV, Muratova AM, Afanasyeva MA, Kravchenko JE, Bhattacharyya A, Kuprash DV . p53-dependent expression of CXCR5 chemokine receptor in MCF-7 breast cancer cells . Scientific Reports . 5 . 5 . 9330 . March 2015 . 25786345 . 4365401 . 10.1038/srep09330 . 2015NatSR...5E9330M .
12. Mitkin NA, Muratova AM, Schwartz AM, Kuprash DV . The A Allele of the Single-Nucleotide Polymorphism rs630923 Creates a Binding Site for MEF2C Resulting in Reduced CXCR5 Promoter Activity in B-Cell Lymphoblastic Cell Lines . Frontiers in Immunology . 7 . 515 . 515 . Nov 2016 . 27909439 . 5112242 . 10.3389/fimmu.2016.00515 . free .
13. Singh S, Singh R, Singh UP, Rai SN, Novakovic KR, Chung LW, Didier PJ, Grizzle WE, Lillard JW . Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines . International Journal of Cancer . 125 . 10 . 2288–2295 . November 2009 . 19610059 . 3600527 . 10.1002/ijc.24574 .