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

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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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Figure 1: Fever-range thermal stress enhances HEV adhesion and homing of lymphocytes to lymphoid organs with HEV structures.
Figure 2: Fever-range thermal stress enhances lymphocyte-HEV interactions.
Figure 3: Fever-range thermal stress selectively increases the expression of ICAM-1 and CCL21 on HEVs.
Figure 4: CCL21 is required for the thermal stimulation of lymphocyte trafficking across HEVs.
Figure 5: ICAM-1 is required for the thermal enhancement of trafficking across HEVs.
Figure 6: IL-6 mediates the thermal stimulation of ICAM-1 expression and homing of lymphocytes across HEVs.
Figure 7: Thermal induction of ICAM-1 and lymphocyte homing does not occur in IL-6-deficient mice.
Figure 8: IL-6 trans signaling mediates the thermal enhancement of ICAM-1 expression and lymphocyte homing in HEVs.

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.


  1. 1

    Girard, J.P. & Springer, T.A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol. Today 16, 449–457 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

    CAS  Article  Google Scholar 

  3. 3

    von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Miyasaka, M. & Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat. Rev. Immunol. 4, 360–370 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Rosen, S.D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Engelhardt, B. & Wolburg, H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur. J. Immunol. 34, 2955–2963 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Kluger, M.J. Fever: role of pyrogens and cryogens. Physiol. Rev. 71, 93–127 (1991).

    CAS  Article  Google Scholar 

  8. 8

    Hasday, J.D., Fairchild, K.D. & Shanholtz, C. The role of fever in the infected host. Microbes Infect. 2, 1891–1904 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Appenheimer, M.M., Chen, Q., Girard, R., Wang, W.C. & Evans, S.S. Impact of fever-range thermal stress on lymphocyte-endothelial adhesion and lymphcoyte trafficking. Immunol. Invest. 34, 295–323 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Ostberg, J.R. & Repasky, E.A. Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function. Cancer Immunol. Immunother. 55, 292–298 (2006).

    Article  Google Scholar 

  11. 11

    Wang, W.C. et al. Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium. J. Immunol. 160, 961–969 (1998).

    CAS  PubMed  Google Scholar 

  12. 12

    Evans, S.S., Bain, M.D. & Wang, W.C. Fever-range hyperthermia stimulates α4β7 integrin-dependent lymphocyte-endothelial adhesion. Int. J. Hyperthermia 16, 45–59 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Chen, Q. et al. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity 20, 59–70 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Jones, S.A. Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175, 3463–3468 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Jones, S.A. & Rose-John, S. The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex. Biochim. Biophys. Acta 1592, 251–263 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Evans, S.S. et al. Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood 97, 2727–2733 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Chen, Q., Fisher, D.T., Kucinska, S.A., Wang, W.C. & Evans, S.S. Dynamic control of lymphocyte trafficking by fever-range thermal stress. Cancer Immunol. Immunother. 55, 299–311 (2006).

    Article  Google Scholar 

  18. 18

    Shah, A. et al. Cytokine and adhesion molecule expression in primary human endothelial cells stimulated with fever-range hyperthermia. Int. J. Hyperthermia 18, 534–551 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Hasday, J.D. et al. Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-α. J. Appl. Physiol. 90, 90–98 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Choi, J., Enis, D.R., Koh, K.P., Shiao, S.L. & Pober, J.S. T lymphocyte-endothelial cell interactions. Annu. Rev. Immunol. 22, 683–709 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Gauguet, J.M., Rosen, S.D., Marth, J.D. & von Andrian, U.H. Core 2 branching β1,6-N-acetylglucosaminyltransferase and high endothelial cell N-acetylglucosamine-6-sulfotransferase exert differential control over B- and T-lymphocyte homing to peripheral lymph nodes. Blood 104, 4104–4112 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Stevens, S.K., Weissman, I.L. & Butcher, E.C. Differences in the migration of B and T lymphocytes: organ-selective localization in vivo and the role of lymphocyte-endothelial cell recognition. J. Immunol. 128, 844–851 (1982).

    CAS  PubMed  Google Scholar 

  23. 23

    von Andrian, U.H. Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation 3, 287–300 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Kashiwazaki, M. et al. A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions. Int. Immunol. 15, 1219–1227 (2003).

    CAS  Article  Google Scholar 

  25. 25

    Izawa, D. et al. Expression profile of active genes in mouse lymph node high endothelial cells. Int. Immunol. 11, 1989–1998 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Okada, T. et al. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J. Exp. Med. 196, 65–75 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Lehmann, J.C. et al. Overlapping and selective roles of endothelial intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in lymphocyte trafficking. J. Immunol. 171, 2588–2593 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Gerwin, N. et al. Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness. Immunity 10, 9–19 (1999).

    CAS  Article  Google Scholar 

  29. 29

    McEvoy, L.M., Jutila, M.A., Tsao, P.S., Cooke, J.P. & Butcher, E.C. Anti-CD43 inhibits monocyte-endothelial adhesion in inflammation and atherogenesis. Blood 90, 3587–3594 (1997).

    CAS  PubMed  Google Scholar 

  30. 30

    Roebuck, K.A. & Finnegan, A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J. Leukoc. Biol. 66, 876–888 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Modur, V., Li, Y., Zimmerman, G.A., Prescott, S.M. & McIntyre, T.M. Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor α. J. Clin. Invest. 100, 2752–2756 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Romano, M. et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6, 315–325 (1997).

    CAS  Article  Google Scholar 

  33. 33

    Bergo, M., Wu, G., Ruge, T. & Olivecrona, T. Down-regulation of adipose tissue lipoprotein lipase during fasting requires that a gene, separate from the lipase gene, is switched on. J. Biol. Chem. 277, 11927–11932 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Fischer, M. et al. I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat. Biotechnol. 15, 142–145 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Ostberg, J.R., Gellin, C., Patel, R. & Repasky, E.A. Regulatory potential of fever-range whole body hyperthermia on Langerhans cells and lymphocytes in an antigen-dependent cellular immune response. J. Immunol. 167, 2666–2670 (2001).

    CAS  Article  Google Scholar 

  36. 36

    Sallusto, F. & Mackay, C.R. Chemoattractants and their receptors in homeostasis and inflammation. Curr. Opin. Immunol. 16, 724–731 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Mackay, C.R., Marston, W. & Dudler, L. Altered patterns of T cell migration through lymph nodes and skin following antigen challenge. Eur. J. Immunol. 22, 2205–2210 (1992).

    CAS  Article  Google Scholar 

  38. 38

    Tedla, N. et al. Regulation of T lymphocyte trafficking into lymph nodes during an immune response by the chemokines macrophage inflammatory protein (MIP)-1α and MIP-1β. J. Immunol. 161, 5663–5672 (1998).

    CAS  PubMed  Google Scholar 

  39. 39

    Soderberg, K.A. et al. Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proc. Natl. Acad. Sci. USA 102, 16315–16320 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Carman, C.V. & Springer, T.A. Integrin avidity regulation: are changes in affinity and conformation underemphasized? Curr. Opin. Cell Biol. 15, 547–556 (2003).

    CAS  Article  Google Scholar 

  41. 41

    Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat. Immunol. 6, 497–506 (2005).

    CAS  Article  Google Scholar 

  42. 42

    Pachynski, R.K., Wu, S.W., Gunn, M.D. & Erle, D.J. Secondary lymphoid-tissue chemokine (SLC) stimulates integrin α4β7-mediated adhesion of lymphocytes to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) under flow. J. Immunol. 161, 952–956 (1998).

    CAS  PubMed  Google Scholar 

  43. 43

    Reilly, P.L. et al. The native structure of intercellular adhesion molecule-1 (ICAM-1) is a dimer. Correlation with binding to LFA-1. J. Immunol. 155, 529–532 (1995).

    CAS  PubMed  Google Scholar 

  44. 44

    Miller, J. et al. Intercellular adhesion molecule-1 dimerization and its consequences for adhesion mediated by lymphocyte function associated-1. J. Exp. Med. 182, 1231–1241 (1995).

    CAS  Article  Google Scholar 

  45. 45

    Casasnovas, J.M., Stehle, T., Liu, J.H., Wang, J.H. & Springer, T.A. A dimeric crystal structure for the N-terminal two domains of intercellular adhesion molecule-1. Proc. Natl. Acad. Sci. USA 95, 4134–4139 (1998).

    CAS  Article  Google Scholar 

  46. 46

    Sarantos, M.R., Raychaudhuri, S., Lum, A.F., Staunton, D.E. & Simon, S.I. Leukocyte function-associated antigen 1-mediated adhesion stability is dynamically regulated through affinity and valency during bond formation with intercellular adhesion molecule-1. J. Biol. Chem. 280, 28290–28298 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Carman, C.V. & Springer, T.A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004).

    CAS  Article  Google Scholar 

  48. 48

    Shaw, S.K. et al. Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration. J. Exp. Med. 200, 1571–1580 (2004).

    CAS  Article  Google Scholar 

  49. 49

    Naka, T., Nishimoto, N. & Kishimoto, T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 4, S233–S242 (2002).

    Article  Google Scholar 

  50. 50

    Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).

    CAS  Article  Google Scholar 

  51. 51

    Abramoff, M.D., Magelhaes, P.J. & Ram, S.J. Image processing with ImageJ. Biophotonics Int. 11, 36–42 (2004).

    Google Scholar 

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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




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.

Corresponding author

Correspondence to Sharon S Evans.

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The authors declare no competing financial interests.

Supplementary information

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. (PDF 107 kb)

Supplementary Fig. 2

Fever-range thermal stress increases lymphocyte-endothelial interactions and ICAM-1 expression in PP HEVs. (PDF 3098 kb)

Supplementary Fig. 3

Fever-range thermal stress did not change total protein abundance of ICAM-1 or CCL21 expression in PLNs. (PDF 155 kb)

Supplementary Fig. 4

ICAM-1 is required for thermal stimulation of lymphocyte trafficking. (PDF 115 kb)

Supplementary Fig. 5

Model for the molecular mechanisms underlying thermal stimulation of lymphocyte trafficking. (PDF 99 kb)

Supplementary Table 1

Summary of vascular adhesion molecule expression in different organs. (PDF 82 kb)

Supplementary Video 1

Lymphocyte-endothelial interactions in nodal venules of a WBH-treated mouse shown by intravital microscopy. (MOV 2916 kb)

Supplementary Methods (PDF 127 kb)

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Chen, Q., Fisher, D., Clancy, K. et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol 7, 1299–1308 (2006).

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