A chemokine-driven positive feedback loop organizes lymphoid follicles

Abstract

Lymphoid follicles are B-cell-rich compartments of lymphoid organs that function as sites of B-cell antigen encounter and differentiation. 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. Here we show that lymph nodes contain two types of B-cell-rich compartment: follicles containing follicular dendritic cells, and areas lacking such cells. Using gene-targeted mice, we establish that B-lymphocyte chemoattractant (BLC/BCA1) and its receptor, CXCR5, are needed for B-cell homing to follicles in lymph nodes as well as in spleen. We also find that BLC is required for the development of most lymph nodes and Peyer's patches. In addition to mediating chemoattraction, BLC induces B cells to up-regulate membrane lymphotoxin alpha1beta2, a cytokine that promotes follicular dendritic cell development and BLC expression, establishing a positive feedback loop that is likely to be important in follicle development and homeostasis. In germinal centres the feedback loop is overridden, with B-cell lymphotoxin alpha1beta2 expression being induced by a mechanism independent of BLC.

Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified

“…During a normal immune response, activated germinal center T-helper cells express high levels of CXCL13, which induces chemotaxis of cells with upregulated expression of the CXCL13 receptor CXCR5, including IgD-positive B cells and certain T-helper cell subsets. 7,13 This results in B cell entry into the follicle, as well as relocalization of unactivated germinal center T-helper cells and central memory T cells from the paracortex toward the follicles, where they can provide help to B cells during the process of antigen affinity maturation and isotype switching. CXCL13 also induces B cells to upregulate lymphotoxinalpha, which itself promotes CXCL13 expression in follicular dendritic cells, establishing a positive feedback loop thought to be critical in the organization of the lymphoid follicle.…”

“…2,4,5 The expression of CXCL13 by angioimmunoblastic T-cell lymphoma, as documented in our recent publication, 6 provides another piece of evidence linking the tumor cells to germinal center T-helper cells. CXCL13, a chemokine critical for B cell entry into germinal centers, 7 was identified by Kim et al 8 as one of the most highly upregulated genes in the germinal center T-helper cell subset. Kim et al also reported selective upregulation of several transcription factors in germinal center T-helper cells.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Given that the early clustering of LTi cells within the embryo is dependent on CXCL13, and that CXCL13 is detected early in the developing lymph nodes of LT α ‐deficient mice,46, 47 this chemokine represents a key initiator of lymphoid organogenesis that functions upstream of LT β R signalling. At ELFs, CXCL13 and CCL21 regulate B‐cell and T‐cell infiltration and segregation at ELFs 48, 49, 50. Similarly, chemokines CCL19 and CXCL12 drive lymphocyte recruitment and the positioning of follicular DCs, B cells and plasma cells at germinal centres 48.…”

In silico subtraction approach reveals a close lineage relationship between follicular dendritic cells and BP3hi stromal cells isolated from SCID mice

“…4H and Table 1). In CXCR5-deficient mice, LTa is expressed but in the absence of the LTa/CXCL13 feedback-loop the level of LTa is not sufficient for normal development of follicular structures and differentiation of reticular cells into mature FDC [26,27]. Nonetheless, the CXCL13 1 stromal cells upregulate the FDC genes BP3, Enpp2 and Bgn (Fig.…”

“…4E and Table 1). These findings, summarized in Table 1, show the complexity of the development of the reticular cell network which supports the lymphoid structures.Transfer experiments showed that a crosstalk between CXCR5 1 B cells and CXCL13-secreting stromal cells is required for the upregulation of LTa and the development of mature FDC [26,27]. As a consequence, the level of LTa is not sufficient in CXCR5-deficient mice for the development of follicular structures.…”