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A chemokine-driven positive feedback loop organizes lymphoid follicles

Nature volume 406, pages 309–314 (2000)Cite this article

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 follicles1, 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)2,3 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 upregulate membrane lymphotoxin α1β2, a cytokine that promotes follicular dendritic cell development and BLC expression4,5, 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 α1β2 expression being induced by a mechanism independent of BLC.

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Figure 1: BLC genomic locus and lack of BLC mRNA and protein in BLC-/- mice.
Figure 2: Absence of primary follicles and FDCs in BLC-/- mice, and defective homing of CXCR5-/- B cells to lymph node follicles.
Figure 3: Membrane LTα1β2 expression on B cells in peripheral lymphoid tissues and dependence on BLC.
Figure 4: BLC induces LTα1β2 upregulation on B cells in vitro.
Figure 5: Misplaced FDC-containing germinal centres in BLC-/- mice and BLC-independent expression of LTα1β2 on germinal centre B cells.

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Acknowledgements

We are especially grateful to N. Killeen for advice and help in generating the BLC knockout mice; K. Reif and L. Tang for helpful advice; and A. Schmidt and C. Backus for blastocyst transfers. K.M.A. is a HHMI predoctoral fellow, S.A.L. is supported by Human Frontier Science Program, and J.G.C is a Packard fellow. This work was supported by grants from the NIH.

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Author notes

  1. K. Mark Ansel, Vu N. Ngo and Jeffrey L. Browning: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology and Immunology University of California San Francisco, San Francisco, 94143, California, USA

    K. Mark Ansel, Vu N. Ngo, Paul L. Hyman, Sanjiv A. Luther & Jason G. Cyster

  2. Molecular Tumorgenetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, 13092, Germany

    Reinhold Förster & Martin Lipp

  3. DNAX Research Institute, Palo Alto, 94304, California, USA

    Jonathon D. Sedgwick

  4. Biogen Inc., Cambridge , 02142, Massachusetts, USA

    Jeffrey L. Browning

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Correspondence to Jason G. Cyster.

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Ansel, K., Ngo, V., Hyman, P. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles . Nature 406, 309–314 (2000). https://doi.org/10.1038/35018581

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