CXCL13 is an arrest chemokine for B cells in high endothelial venules

B-cell development is orchestrated by complex signaling networks. Rap1 is a member of the Ras superfamily of small GTP-binding proteins and has 2 isoforms, Rap1a and Rap1b. Although Rap1 has been suggested to have an important role in a variety of cellular processes, no direct evidence demonstrates a role for Rap1 in B-cell biology. In this study, we found that Rap1b was the dominant isoform of Rap1 in B cells. We discovered that Rap1b deficiency in mice barely af- The H-chain locus rearranges V, D, and J segments first in the pro-B cells. A successful VDJ H rearrangement leads to the expression of a H chain, which in combination with a surrogate light chain forms the pre-B-cell receptor (pre-BCR). [3][4][5] Signals emanating from the pre-BCR control pro-to pre-B-cell transition. Subsequently, pre-B cells undergo rearrangement of L-chain V and J gene segments. A successfully rearranged L chain, in combination with the previously rearranged H chain, generates a surface IgM form of the BCR. B cells with a functional BCR quickly progress into immature B cells and emerge from bone marrow (BM) into the spleen. 1,2 Maturation of newly formed immature B cells in the spleen involves several steps that are regulated by signals from the BCR. 6,7 Immature B cells from BM emerge into the spleen as transitional B cells of type 1 (T1). T1 B cells develop into the transitional B cells of type 2 (T2). Ultimately, T2 B cells give rise to 2 subsets of long-lived mature B cells, follicular (FO) B cells and marginal zone (MZ) B cells. The recirculating FO B cells localize to the B-lymphoid follicles of the spleen and lymph node, 8 whereas the mostly nonrecirculating MZ B cells come to reside primarily in the marginal zones of the splenic lymphoid nodules. 9-11 A third subset of mature B cells, selfrenewing B1 B cells, are derived from fetal liver B-cell progenitors and are enriched in the peritoneal and pleural cavities. 12 In addition to signals emanating from the BCR, signals derived from chemokines regulate development and compartmentalization of different subsets of mature B cells. 13,14 Defects in chemokine signaling often reduce B-cell chemotaxis, leading to an impairment of the development of mature B-cell subsets. [15][16][17] Rap1 is a member of the Ras superfamily of small GTP-binding proteins. 18,19 Rap1 has 2 isoforms, Rap1a and Rap1b, coded by distinct genes. 18 Like other small GTP-binding proteins, GTPbound Rap1 is an active form, whereas the GDP-bound form is an inactive form. Activation of Rap1 is regulated by specific guanine nucleotide exchange factors that promote the dissociation of GDP to facilitate GTP loading. 18,19 The termination of Rap1GTP activity is regulated by Rap1 GTPase-activating proteins (GAPs). Rap1GTP is able to regulate activation of all 3 MAPKs. [20][21][22][23][24][25][26] In some cells, Rap1GTP may competitively interfere with Ras-mediated ERK activation. 20 However, Rap1GTP is also able to directly activate the mitogen-activated protein kinase kinase (MEK)/extracellular signalregulated kina...

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development

Chen

Podd

et al. 2008

“…As chemokines are in part synthesized by lymphoid stromal cells including FRCs, CCL21 detected in tissue sections could be preferentially localized inside FRC conduits for transport to the HEV network, where it may contribute to lymphocyte recruitment. [30][31][32][33][34] Thus, 2-P microscopy imaging helps to uncouple in vitro chemoattractant responsiveness from in vivo chemoattractant responsiveness, which depends on the "usable" chemokine levels available to trafficking lymphocytes. At the same time, these data highlight the importance of chemokine receptor levels in responding to presumably limited amounts of stromal chemokine.…”

Section: Discussionmentioning

confidence: 99%

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions

Coelho

Natale

Soriano

et al. 2013

Key Points• CXCR5, but not CXCR4 or CCR7, acts with LFA-1 to mediate random B-cell migration in the T-cell area and B-cell follicles.• In contrast, stromal guidance during B-cell migration is LFA-1 independent and CXCR5 independent.It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not a4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute. (Blood. 2013;121(20):4101-4109)

“…Generally, CXCR5 induces recruitment of circulating naive B cells to follicles. 15,[18][19][20] Regarding the microanatomic positioning within the germinal center (GC), dark and light zones of the GC can be distinguished, and centroblasts localize to the dark zones via CXCR4. There, centroblasts rapidly divide and undergo somatic hypermutation of the antibody variable region genes.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia

Bürkle

Niedermeier

Schmitt‐Gräff

et al. 2007

205

158

IntroductionB-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of a monoclonal population of CD5 ϩ neoplastic B cells in blood, secondary lymphoid tissues, and the marrow. 1 Chemokines are essential for lymphocyte trafficking and homing during immune surveillance. 2 However, the mechanisms that regulate the dissemination of CLL cells to different tissue compartments are largely unknown. Earlier, we reported that the chemokine receptor CXCR4 induces spontaneous migration of CLL cells beneath marrow stromal cells. 3 More recently, the importance of CXCR4 for homing of neoplastic B cells to the marrow was confirmed in vivo. 4 We also reported that a small proportion of monocyte-derived cells from the blood of CLL patients differentiates into large, adherent nurselike cells (NLCs) that attract CLL cells and protect them from undergoing spontaneous or druginduced cell death. [5][6][7] NLCs express high levels of CD68 and can be detected in secondary lymphoid tissues from patients with CLL. 6 NLCs therefore appear to be an integral part of the CLL microenvironment within secondary lymphoid tissues, and may be comparable with lymphoma-associated macrophages (LAMs) in follicular lymphoma. 8 The molecules involved in the cross talk between CLL cells and NLCs are only partially understood. NLCs secrete CXCL12 and thereby attract CLL cells and support their survival. 5,9 Moreover, NLCs express B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF), a proliferation-inducing ligand (APRIL), 9 CD31, and plexin-B1 10 that also protect CLL cells from apoptosis, indicating that NLCs use multiple distinct pathways to support CLL cell survival.In contrast to CXCR4, which is broadly expressed by normal and malignant hematopoietic and nonhematopoietic cells, 11 the chemokine receptor CXCR5 is expressed only by mature recirculating B cells, a small subset of CD4 ϩ and CD8 ϩ T cells, and skin-derived migratory dendritic cells (reviewed in Muller et al 12 ). CXCR5 initially was isolated from Burkitt lymphoma and designated Burkitt lymphoma receptor 1 (BLR1). 13 CXCR5 gene-deleted mice display defective formation of primary follicles and germinal centers in the spleen and Peyer patches, and lack inguinal lymph nodes. 14 Subsequently, the ligand for CXCR5 was identified and termed B-cell-attracting chemokine 1 (BCA-1). 15,16 According to our current chemokine classification, BCA-1 now is designated CXCL13. 17 CXCL13 is a homeostatic chemokine that is constitutively secreted by stromal cells in B-cell areas of secondary lymphoid tissues (follicles), where B cells encounter antigen and differentiate. Generally, CXCR5 induces recruitment of circulating naive B cells to follicles. 15,[18][19][20] Regarding the microanatomic positioning within the germinal center (GC), dark and light zones of the GC can be distinguished, and centroblasts localize to the dark zones via CXCR4. There, centroblasts rapidly divide and undergo somatic hypermutation of the antibody variable region genes. Subsequently, t...