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Regulation of TH2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells

Abstract

Although cognate encounters between antigen-bearing dendritic cells (DCs) that express the chemokine receptor CCR7 and CCR7+ naive T cells take place in the T cell zone of lymph nodes, it is unknown whether the colocalization of DCs and T cells in the T cell area is required for the generation of effector cells. Here we found that after infection with an intestinal nematode, antigen-bearing DCs and CD4+ T cells upregulated the chemokine receptor CXCR5 and localized together outside the T cell zone by a mechanism dependent on the chemokine CXCL13, B cells and lymphotoxin. Notably, lymphotoxin-expressing B cells, CXCR5-expressing DCs and T cells, and CXCL13 were also necessary for development of interleukin 4 (IL-4)-producing type 2 helper T cells (TH2 cells), which suggests that TH2 differentiation can initiate outside the T cell zone.

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Figure 1: DCs migrate to the peri- and interfollicular areas of lymph nodes after infection with H. polygyrus.
Figure 2: Mature DCs bearing H. polygyrus antigens express CXCR5 and show more responsiveness to CXCL13 and less responsiveness to CCL19.
Figure 3: DC positioning in the lymph nodes and the development of TH2 cells after infection with H. polygyrus is controlled by CXCL13 and not CCL19 or CCL21a.
Figure 4: Development of IL-4-producing T cells after infection with H. polygyrus is controlled by CXCR5-expressing DCs.
Figure 5: CXCR5 is expressed by lymph node TFH and TH2 cells and is required for the development of TFH and Th2 cells after infection with H. polygyrus.
Figure 6: B cell depletion alters the site of colocalization of DCs and CD4+ T cells in the lymph node and prevents the development of TFH cells and TH2 cells but not of TH1 cells.
Figure 7: Blockade of lymphotoxin downregulates CXCL13 expression, prevents colocalization of DCs and T cells in the B cell area and impairs the development of TH2 cells in lymph nodes of H. polygyrus–infected mice.
Figure 8: B cell–derived lymphotoxin facilitates the migration of DCs to the B cell area of lymph nodes after infection with H. polygyrus and modulates TH2 development.

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Acknowledgements

We thank L. LaMere, A. Bucher and K. Martin for management of animal breeding and genotyping; the University of Rochester Flow Facility Core for cell sorting; the tetramer facility of the US National Institutes of Health for influenza virus nucleoprotein–specific CD4 tetramers; M. Mohrs (Trudeau Institute) for B6 4get (IL-4 reporter) and 4getμMT mice; J. Kearney (University of Alabama-Birmingham) for MD4μMT mice; and J. Cyster (University of California, San Francisco) for plt mice. Supported by the University of Rochester and the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (AI068056 and AI078907 to F.E.L., and AI061511 to T.D.R.).

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B.L., A.B.-T., F.E.L. and T.D.R. contributed to the design of the experiments and the writing of the manuscript; B.L. did all experiments with help from A.B.-T.; J.L.B. and R.D. provided advice, discussions and reagents; and all authors reviewed the manuscript before submission.

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Correspondence to Frances E Lund.

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Competing interests

R.D. and J.B. are present (J.B.) or former (R.D.) employees of Biogen Idec, which has a financial interest in anti-CD20 therapy for humans.

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León, B., Ballesteros-Tato, A., Browning, J. et al. Regulation of TH2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells. Nat Immunol 13, 681–690 (2012). https://doi.org/10.1038/ni.2309

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