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Regulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling

Author

Listed:
  • Wenji Piao

    (University of Maryland School of Medicine)

  • Yanbao Xiong

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Konrad Famulski

    (University of Alberta)

  • C. Colin Brinkman

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Lushen Li

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Nicholas Toney

    (University of Maryland School of Medicine)

  • Chelsea Wagner

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Vikas Saxena

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Thomas Simon

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Jonathan S. Bromberg

    (University of Maryland School of Medicine
    University of Maryland School of Medicine
    University of Maryland School of Medicine)

Abstract

Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM). The function of individual signaling pathways for different leukocyte subsets is currently unknown. Here, we show that LTβR signals predominantly via the constitutive and ligand-driven non-classical NIK pathway. Targeting LTβR-NIK by an LTβR-derived decoy peptide (nciLT) suppresses the production of chemokines CCL21 and CXCL12, and enhances the expression of classical NFκB-driven VCAM-1 and integrin β4 to retain T cells on LEC and precludes T cell and dendritic cell TEM. nciLT inhibits contact hypersensitivity (CHS) at both the sensitization and elicitation stages, likely by inhibiting leukocyte migration. By contrast, targeting LTβR-classical NFκB signaling during the elicitation and resolution stages attenuates CHS, possibly by promoting leukocyte egress. These findings demonstrate the importance of LTβR signaling in leukocyte migration and LEC and lymphatic vessel function, and show that antagonist peptides may serve as lead compounds for therapeutic applications.

Suggested Citation

  • Wenji Piao & Yanbao Xiong & Konrad Famulski & C. Colin Brinkman & Lushen Li & Nicholas Toney & Chelsea Wagner & Vikas Saxena & Thomas Simon & Jonathan S. Bromberg, 2018. "Regulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05412-0
    DOI: 10.1038/s41467-018-05412-0
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    Cited by:

    1. Wenji Piao & Long Wu & Yanbao Xiong & Gregory C. Zapas & Christina M. Paluskievicz & Robert S. Oakes & Sarah M. Pettit & Margaret L. Sleeth & Keli L. Hippen & Jessica Schmitz & Philipp Ivanyi & Amol C, 2024. "Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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