Disease relevance of Blr1

• CXCR5-/- mice showed a normal production of IgM and IgG acutely after infection with vesicular stomatitis virus (VSV) and developed VSV-specific germinal centers [1].
• There is also accumulating evidence for the involvement of CXCR5 in the formation of ectopic follicles as observed in lymphomas or autoimmune diseases [2].
• Lymphopenia is noticeably delayed in mice lacking CCR7, whereas CXCR5 knockout mice show a significant reduction of lymphocyte accumulation in secondary lymphoid organs that are infrequently present in these mice [3].
• Furthermore, pertussis toxin, which is known to inhibit signaling via G protein-coupled chemokines, inhibited the migration of contact-activated peritoneal B-1 cells to the lymphoid tissues, probably due to BLR-1 (Burkitt lymphoma receptor-1) [4].
• OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice [5].

High impact information on Blr1

• Blr1 mutant mice lack inguinal lymph nodes and possess no or only a few phenotypically abnormal Peyer's patches [6].
• Reciprocally, overexpression of CXCR5, the receptor for the B-zone chemokine CXCL13, is sufficient to overcome antigen-induced B-cell movement to the T zone [7].
• CXC chemokine receptor-5 (CXCR5) is required for B-cell migration to splenic follicles, but the requirements for homing to B-cell areas in lymph nodes remain to be defined [8].
• We show here that CXCR5/CXCL13 signaling activates alpha4beta1 integrin on CD4+CD3- cells [9].
• CD4+CD3- cells induce Peyer's patch development: role of alpha4beta1 integrin activation by CXCR5 [9].

Biological context of Blr1

• These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization [10].
• Herein, we analyzed the surface phenotype of skin-derived migratory DC and found that 15-35% of MHC class II(high) cells showed high levels of expression of CXCR5 but expressed low levels of DEC205, a suggested characteristic of dermal-type DC in mice [11].
• CXCR5 was detected by flow cytometry on transduced cells, which responded to CXCL13 in vitro in chemotaxis assays (3-fold over nontransduced BMDC, p < 0.01) [11].
• In addition, CCR7 and CXCR5 have been identified as useful markers in the classification of functionally distinct subsets of T-helper cells, which will lead to a better understanding of T cell memory and T cell effector function in lymphoid system homeostasis and disease [2].
• Blr-1 consists of two exons encoding a protein of 374 amino acid residues which shows 83% identity with the human homologue [12].

Anatomical context of Blr1

• Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5 [13].
• Due to an impaired migration of B cells into the white pulp, CXCR5-/- CCR7-/- mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen [10].
• We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area [14].
• Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells [14].
• Skin-derived migratory dendritic cells (DC), in contrast to bone marrow-derived DC (BMDC), express CXCR5, respond to the chemokine CXC ligand 13 (CXCL13) in vitro, and are capable of migrating to B cell zones (BCZ) in lymph nodes (LN) in vivo [11].

Associations of Blr1 with chemical compounds

• Here, we show markedly decreased B-1 B cell numbers in the peritoneal cavity of CXCR5-/- and CXCR5-/-CCR7-/- double-deficient mice paralleled by reduced antigen-induced phosphorylcholine-specific immunoglobulin (Ig)M responses after intraperitoneal (i.p.) administration of streptococcal antigen [15].

Regulatory relationships of Blr1

• Compared to naïve, type-1 and type-2 populations had reduced CCR7 and enhanced CXCR5 transcripts, consistent with a shift to memory cells [16].

Other interactions of Blr1

• We demonstrate that CD3- CD4+ IL-7R alpha hi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development [10].
• In addition, DN Treg cells have been shown to express several molecules uncommon to other Treg cell subsets, such as IFN-gamma, TNF-alpha, Ly6A, FcRgamma, and CXCR5, which may contribute to their unique regulatory ability [17].
• Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice [18].
• The chemokine receptor CXCR5 and its ligand CXCL13 define the structure of B cell follicles within secondary lymphoid organs [1].
• Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice [19].

Analytical, diagnostic and therapeutic context of Blr1

• Moreover, CXCR5 directs BMDC to BCZ of LN in vivo and modifies Ag-specific immune responses induced by BMDC vaccination [11].
• Adoptive transfer of CXCR5-deficient, VSV-specific B and Th cells demonstrated that CXCR5 expression on both B and Th cells is required for an efficient Ig class switch [1].
• CXCR5 was particularly prominent in pancreatic carcinoma cell lines and was also detected by immunohistochemistry in 7 of 18 human pancreatic carcinoma tissues [20].
• These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation [21].
• PCR experiments confirmed the differential expression of CXCR5 [22].

References