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Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism

Nature Immunology volume 7, pages 12991308 (2006) | Download Citation

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Abstract

Fever is an evolutionarily conserved response during acute inflammation, although its physiological benefit is poorly understood. Here we show thermal stress in the range of fever temperatures increased the intravascular display of two 'gatekeeper' homing molecules, intercellular adhesion molecule 1 (ICAM-1) and CCL21 chemokine, exclusively in high endothelial venules (HEVs) that are chief portals for the entry of blood-borne lymphocytes into lymphoid organs. Enhanced endothelial expression of ICAM-1 and CCL21 was linked to increased lymphocyte trafficking across HEVs. A bifurcation in the mechanisms controlling HEV adhesion was demonstrated by evidence that the thermal induction of ICAM-1 but not of CCL21 involved an interleukin 6 trans-signaling pathway. Our findings identify the 'HEV axis' as a thermally sensitive alert system that heightens immune surveillance during inflammation by amplifying lymphocyte trafficking to lymphoid organs.

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Change history

  • 10 November 2006

    In the version of this article initially published online, the label for the bottom row of Figure 8d is missing. It should read ‘H-IL-6’. The error has been corrected for all versions of the article.

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Acknowledgements

We thank J.D. Black and E.A. Repasky for discussions and comments on the manuscript; M. Miyasaka and T. Tanaka (Osaka University) for antiserum to mouse Duffy antigen–related receptor for chemokines; P.K. Wallace and E.A. Timm for assistance with flow cytometry of leukocyte subsets; and E.L. Hurley for technical support for confocal microscopy. Supported by the US National Institutes of Health (CA79765 and CA094045 to S.S.E.; AI061663 and AI069259 to U.V.A.; DK33886 and CA85580 to H.B.; and CA16056 to Roswell Park Cancer Institute), the Department of Defense (W81XWH-04-1-0354 to Q.C.), the Roswell Park Alliance Foundation (to S.S.E.), the Leukocyte Migration Core of the Harvard Skin Disease Research Center (P30 AR 42689 to U.H.v.A.) and the Deutsche Forschungsgemeinschaft (Bonn, Germany; SFB414, TPB5 to S.R.J.).

Author information

Affiliations

  1. Departments of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

    • Qing Chen
    • , Daniel T Fisher
    • , Kristen A Clancy
    • , Wan-Chao Wang
    • , Emily Unger
    •  & Sharon S Evans
  2. The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts, 02115, USA.

    • Jean-Marc M Gauguet
    •  & Ulrich H von Andrian
  3. Department of Biochemistry, Christian Albrechts University Kiel, D-24098 Kiel, Germany.

    • Stefan Rose-John
  4. Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

    • Heinz Baumann

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Contributions

Q.C. and S.S.E. conceptualized and designed the research; S.S.E. supervised the research; Q.C. did all experiments unless stated otherwise; D.T.F. contributed to the experimental design for quantitative image analysis and did the phenotypic analysis in short-term homing assays and enzyme-linked immunosorbent assay for ICAM-1; K.A.C assisted in immunofluorescence staining and kinetic analysis in short-term homing assays; E.U. contributed to the analysis of ICAM-1 staining; W.-C.W. did frozen-section adherence assays and provided technical assistance for organ retrieval; U.H.v.A. and J.-M.G. helped with intravital microscopy studies; S.R.J. provided the hyper-IL-6 expression construct; H.B. provided recombinant hyper-IL-6 and contributed to discussions regarding IL-6 regulation of lymphocyte trafficking; and all authors contributed to discussions and to the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sharon S Evans.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Fever-range thermal stress enhances lymphocyte homing to lymphoid organs with HEV structures without altering the cellular composition of cells recruited into PLNs.

  2. 2.

    Supplementary Fig. 2

    Fever-range thermal stress increases lymphocyte-endothelial interactions and ICAM-1 expression in PP HEVs.

  3. 3.

    Supplementary Fig. 3

    Fever-range thermal stress did not change total protein abundance of ICAM-1 or CCL21 expression in PLNs.

  4. 4.

    Supplementary Fig. 4

    ICAM-1 is required for thermal stimulation of lymphocyte trafficking.

  5. 5.

    Supplementary Fig. 5

    Model for the molecular mechanisms underlying thermal stimulation of lymphocyte trafficking.

  6. 6.

    Supplementary Table 1

    Summary of vascular adhesion molecule expression in different organs.

  7. 7.

    Supplementary Methods

Videos

  1. 1.

    Supplementary Video 1

    Lymphocyte-endothelial interactions in nodal venules of a WBH-treated mouse shown by intravital microscopy.

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DOI

https://doi.org/10.1038/ni1406

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