Alternative titles; symbols
HGNC Approved Gene Symbol: CXCR5
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,883,892-118,897,787 (from NCBI)
Dobner et al. (1992) and Kaiser et al. (1993) identified a novel member of the G protein-coupled receptor family termed BLR1 (BLR1 having been identified from Burkitt lymphoma).
B lymphocytes recirculate between B cell-rich compartments (follicles or B zones) in secondary lymphoid organs, surveying for antigen. After antigen binding, B cells move to the boundary of B and T zones to interact with T-helper cells. Reif et al. (2002) demonstrated that antigen-engaged B cells have increased expression of CCR7 (600242), the receptor for the T-zone chemokines CCL19 (602227) and CCL21 (602737), and that they exhibit increased responsiveness to both chemoattractants. In mice lacking lymphoid CCL19 and CCL21 chemokines, or with B cells that lack CCR7, antigen engagement fails to cause movement to the T zone. Using retroviral-mediated gene transfer, the authors demonstrated that increased expression of CCR7 is sufficient to direct B cells to the T zone. Reciprocally, overexpression of CXCR5, the receptor for the B-zone chemokine CXCL13 (also known as BLC), is sufficient to overcome antigen-induced B-cell movement to the T zone. Reif et al. (2002) concluded that their findings defined the mechanism of B-cell relocalization in response to antigen, and established that cell position in vivo can be determined by the balance of responsiveness to chemoattractants made in separate but adjacent zones.
Chan et al. (2003) investigated the expression of chemokines and chemokine receptors in eyes with primary intraocular B-cell lymphoma (PIOL). All 3 PIOL eyes showed similar pathology, with typical diffuse large B-lymphoma cells between the retinal pigment epithelium (RPE) and Bruch membrane. The eyes also showed a similar chemokine profile with the expression of CXCR4 (162643) and CXCR5 in the lymphoma cells. CXCL13 (BLC) and CXCL12 (600835) transcripts were found only in the RPE and not in the malignant cells. No chemokine expression was detected on the RPE cells of a normal control eye. Since chemokines and chemokine receptors selective for B cells were identified in RPE and malignant B cells in eyes with PIOL, inhibition of B-cell chemoattractants might be a future strategy for the treatment of PIOL.
The germinal center (GC) is organized into dark and light zones. B cells in the dark zone, called centroblasts, undergo rapid proliferation and somatic hypermutation of their antibody variable genes. Centroblasts then become smaller, nondividing centrocytes and undergo selection in the light zone based on the affinity of their surface antibody for the inducing antigen. The light zone also contains helper T cells and follicular dendritic cells that sequester antigen. Failure to differentiate results in centrocyte apoptosis, whereas centrocytes that bind antigen and receive T-cell help emigrate from the GC as long-lived plasma cells or memory B cells. Some centrocytes may also return to the dark zone for further proliferation and mutation. Using genetic and pharmacologic approaches, Allen et al. (2004) showed that CXCR4 was essential for GC dark and light zone segregation. In the presence of the antiapoptotic BCL2 (151430), B cells had robust chemotactic responses to the CXCR4 ligand, CXCL12, as well as to CXCL13, the ligand for CXCR5. CXCL12 was more abundant in the dark zone, and CXCR4 was more abundant on centroblasts than centrocytes. In contrast, CXCR5 helped direct cells to the CXCL13-positive light zone, but was not essential for segregation of the 2 zones. CXCL13 and CXCR5 were required for correct positioning of the light zone. Allen et al. (2004) concluded that these chemokines and their receptors are critical for movement of cells to different parts of the GC and for creating the distinct histologic appearance of the GC.
Using flow cytometry and immunohistochemistry, Cagigi et al. (2008) found that human immunodeficiency virus (HIV)-1 (see 609423)-seropositive patients, particularly those with low CD4 (186940)-positive T-cell counts, had reduced expression of CXCR5 on B cells, whereas expression of its ligand, CXCL13, was increased. CXCL13 was secreted upon B-cell activation. CXCL13-positive B cells were present in lymph nodes of HIV-1-seropositive patients, but not in control tissue. Cagigi et al. (2008) concluded that altered expression of CXCR5 and CXCL13 may be involved in B-cell dysfunction during HIV-1 infection.
He et al. (2016) identified a subset of functionally exhausted Cd8-positive T cells that expressed Cxcr5 and had a critical role in controlling viral replication in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Cxcr5-positive/Cd8-positive T cells were able to migrate into B-cell follicles and expressed lower levels of inhibitory receptors, had more potent cytotoxicity, and produced more Ifng (147570) and Tnf (191160) than Cxcr5-negative/Cd8-positive T cells. The Id2 (600386)-E2a (TCF3; 147141) signalling axis had an important regulatory role in the generation of the Cxcr5-positive/Cd8-positive T-cell subset. A virus-specific CXCR5-positive/CD8-positive T-cell subset was also present in patients with HIV, and its number was inversely correlated with viral load. He et al. (2016) concluded that the CXCR5-positive subset of exhausted CD8-positive T cells has a pivotal role in control of viral replication.
Im et al. (2016) showed that Cxcr5-positive/Cd8-positive T cells proliferated after blockade of the Pd1 (PDCD1; 600244) pathway in mice chronically, but not acutely, infected with LCMV. Flow cytometric and gene expression analyses showed that Cxcr5-positive/Pd1-positive/Cd8-positive T cells expressed higher levels of costimulatory molecules, such as Cd28 (186760) and Icos (604558), and lower levels of inhibitory receptors, such as Cd244 (605554) and Havcr (606518), compared with Cxcr5-negative/Cd8-positive T cells. Cxcr5-positive/Pd1-positive/Cd8-positive T cells were able to renew themselves during chronic LCMV infection, resembling stem cells, and also differentiated into terminally exhausted Cd8-positive T cells present in both lymphoid and nonlymphoid tissues. Tcf1 (TCF7; 189908) had a cell-intrinsic and essential role in generation of the Cxcr8-positive/Cd8-positive T-cell subset.
Leong et al. (2016) identified CXCR5-positive/CD8-positive T cells, which they called follicular cytotoxic T (Tfc) cells, that selectively entered B-cell follicles and eradicated infected CXCR5-positive/CD4-positive follicular helper T cells and B cells in mice and humans. Differentiation of Tfc cells required the transcription factors BCL6 (109565), E2A, and TCF1 and was blocked by the transcriptional regulators BLIMP1 (PRDM1; 603423), ID2, and ID3 (600277).
Ma and Tangye (2016) compared and contrasted the results obtained by He et al. (2016), Im et al. (2016), and Leong et al. (2016) concerning the activity of CXCR5-positive/CD8-positive T cells. These cells are present in secondary lymphoid tissues, can overcome cytotoxic T-cell exhaustion, at least in part through reduced PD1 expression, and can control chronic viral infections. CD8-positive T cells not expressing CXCR5 have the exhausted phenotype.
Forster et al. (1996) described the phenotype of gene-targeted mice lacking the putative chemokine receptor Blr1. In normal mice, this receptor is expressed on mature B cells and a subpopulation of T helper cells. Blr1-mutant mice lack inguinal lymph nodes and possess no or only a few phenotypically abnormal Peyer patches. The migration of lymphocytes into splenic follicles was severely impaired, resulting in morphologically altered primary lymphoid follicles. Furthermore, activated B cells failed to migrate from the T cell-rich zone into B-cell follicles of the spleen, and despite high numbers of germinal center founder cells, no functional germinal centers developed in this organ. These results identified BLR1 as the first G protein-coupled receptor involved in B cell migration and localization of these cells within specific anatomic compartments.
CXCR5 was known to be required for B cell migration to splenic follicles, but the requirements for homing to B-cell areas and lymph nodes remained to be defined. Ansel et al. (2000) demonstrated that lymph nodes contain 2 types of B cell-rich compartment: follicles containing follicular dendritic cells, and areas lacking such cells. Ansel et al. (2000) generated mice deficient in the B-lymphocyte chemoattractant (BLC; 605149), for which CXCR5 is the receptor, by targeted disruption. BLC-deficient mice were similar in appearance to mice deficient in CXCR5. However, CXCR5-deficient mice have less severe deficiency in Peyer patches. Using BLC-deficient mice, Ansel et al. (2000) established that BLC and CXCR5 are needed for B-cell homing to follicles in lymph nodes as well as in spleen. They also found that BLC is required for the development of most lymph nodes and Peyer patches. In addition to mediating chemoattraction, BLC induces B cells to upregulate membrane lymphotoxin alpha-1-beta-2 (see 600978), a cytokine that promotes follicular dendritic cell development and BLC expression, establishing a positive feedback loop thought to be important in follicle development and homeostasis. In germinal centers, the feedback loop is overridden, with B cell lymphotoxin alpha-1-beta-2 expression being induced by a mechanism independent of BLC.
Voigt et al. (2000) found that B cells and dendritic cells do colocalize, albeit aberrantly, even in the absence of CXCR5. In mice lacking Cxcr5, both cell types were found in a broad ring around the sinuses of the marginal zones. Voigt et al. (2000) concluded that in Cxcr5-deficient mice, the organization of splenic primary follicles is severely impaired. However, within the T cell zone a microenvironment is built up, which provides all requirements needed for the affinity maturation to take place.
Prinz et al. (2003) found that in mice deficient in Cxcr5 the follicular dendritic cells (FDCs) are juxtaposed to major splenic nerves and the transfer of intraperitoneally-administered prions (see 176640) into the spinal cord is accelerated. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves; transfer of Cxcr5 -/- bone marrow to wildtype mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to Cxcr5 -/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signaling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in Cxcr5 -/- mice. Prinz et al. (2003) concluded that their data suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.
Allen, C. D. C., Ansel, K. M., Low, C., Lesley, R., Tamamura, H., Fujii, N., Cyster, J. G. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immun. 5: 943-952, 2004. [PubMed: 15300245] [Full Text: https://doi.org/10.1038/ni1100]
Ansel, K. M., Ngo, V. N., Hyman, P. L., Luther, S. A., Forster, R., Sedgwick, J. D., Browning, J. L., Lipp, M., Cyster, J. G. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406: 309-314, 2000. [PubMed: 10917533] [Full Text: https://doi.org/10.1038/35018581]
Cagigi, A., Mowafi, F., Dang, L. V. P., Tenner-Racz, K., Atlas, A., Grutzmeier, S., Racz, P., Chiodi, F., Nilsson, A. Altered expression of the receptor-ligand pair CXCR5/CXCL13 in B cells during chronic HIV-1 infection. Blood 112: 4401-4410, 2008. [PubMed: 18780835] [Full Text: https://doi.org/10.1182/blood-2008-02-140426]
Chan, C.-C., Shen, D., Hackett, J. J., Buggage, R. R., 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: 421-426, 2003. [PubMed: 12578791] [Full Text: https://doi.org/10.1016/S0161-6420(02)01737-2]
Dobner, T., Wolf, I., Emrich, T., Lipp, M. Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt's lymphoma. Europ. J. Immun. 22: 2795-2799, 1992. [PubMed: 1425907] [Full Text: https://doi.org/10.1002/eji.1830221107]
Forster, R., Mattis, A. E., 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: 1037-1047, 1996. [PubMed: 8978608] [Full Text: https://doi.org/10.1016/s0092-8674(00)81798-5]
He, R., Hou, S., Liu, C., Zhang, A., Bai, Q., Han, M., Yang, Y., Wei, G., Shen, T., Yang, X., Xu, L., Chen, X., and 15 others. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537: 412-416, 2016. Note: Erratum: Nature 540: 470 only, 2016. [PubMed: 27501245] [Full Text: https://doi.org/10.1038/nature19317]
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., Sharpe, A. H., Freeman, G. J., Germain, R. N., Nakaya, H. I., Xue, H.-H., Ahmed, R. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537: 417-421, 2016. [PubMed: 27501248] [Full Text: https://doi.org/10.1038/nature19330]
Kaiser, E., Forster, R., Wolf, I., Ebensperger, C., Kuehl, W. M., Lipp, M. The G protein-coupled receptor BLR1 is involved in murine B cell differentiation and is also expressed in neuronal tissues. Europ. J. Immun. 23: 2532-2539, 1993. [PubMed: 8405054] [Full Text: https://doi.org/10.1002/eji.1830231023]
Leong, Y. A., Chen, Y., Ong, H. S., Wu, D., Man, K., Deleage, C., Minnich, M., Meckiff, B. J., Wei, Y., Hou, Z., Zotos, D., Fenix, K. A., and 25 others. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nature Immun. 17: 1187-1196, 2016. [PubMed: 27487330] [Full Text: https://doi.org/10.1038/ni.3543]
Ma, C. S., Tangye, S. G. Cytotoxic T cells that escape exhaustion. Nature 537: 312-314, 2016. [PubMed: 27556942] [Full Text: https://doi.org/10.1038/nature19428]
Prinz, M., Heikenwalder, M., Junt, T., Schwarz, P., Glatzel, M., Heppner, F. L., Fu, Y.-X., Lipp, M., Aguzzi, A. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425: 957-962, 2003. [PubMed: 14562059] [Full Text: https://doi.org/10.1038/nature02072]
Reif, K., Ekland, E. H., Ohl, L., Nakano, H., Lipp, M., Forster, R., Cyster, J. G. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416: 94-99, 2002. [PubMed: 11882900] [Full Text: https://doi.org/10.1038/416094a]
Voigt, I., Camacho, S. A., de Boer, B. A., Lipp, M., Forster, R., Berek, C. CXCR5-deficient mice develop functional germinal centers in the splenic T cell zone. Europ. J. Immun. 30: 560-567, 2000. [PubMed: 10671212] [Full Text: https://doi.org/10.1002/1521-4141(200002)30:2<560::AID-IMMU560>3.0.CO;2-T]