Fever and the thermal regulation of immunity: the immune system feels the heat

Nature Reviews Immunology volume 15, pages335–349(2015)Cite this article

Subjects

Key Points

  • The hallmark fever response during infection and disease has been maintained throughout hundreds of millions of years in endothermic (warm-blooded) and ectothermic (cold-blooded) species.

  • Febrile temperatures boost the probability of an effective immune response by stimulating both the innate and the adaptive arms of the immune system.

  • The pyrogenic cytokine interleukin-6 (IL-6) contributes to two phases of the febrile response: it elevates the core body temperature via thermoregulatory autonomic mechanisms, and it also serves as a thermally sensitive effector molecule that amplifies lymphocyte trafficking into lymphoid organs.

  • There is emerging evidence that adrenergic signalling pathways associated with thermogenesis can greatly influence immune cell function.

  • Thus, the thermal element of fever serves as a systemic alert system that broadly promotes immune surveillance in the setting of infection and disease.

Abstract

Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Figure 1: The induction of fever during infection.
Figure 2: Response of innate immune cells to thermal stress.
Figure 3: Fever-range thermal stress and the adaptive immune response.
Figure 4: Thermal stress acts through IL-6 trans-signalling to improve lymphocyte trafficking into lymph nodes.
Figure 5: Cold stress stimulates nerve-driven modulation of thermogenesis and antitumour immunity.

References

  1. 1

    Celsus, A. C. A. Cornelius Celsus of Medicine: in Eight Books (ed. Grieve, J.) (D. Wilson & T. Durham, 1756). This set of books summarizes the work of Celsus (approximately 25 BC to 50 AD), who described the four cardinal signs of inflammation.

    Google Scholar 

  2. 2

    Kluger, M. J. Phylogeny of fever. Fed. Proc. 38, 30–34 (1979).

    CAS  PubMed  Google Scholar 

  3. 3

    Earn, D. J., Andrews, P. W. & Bolker, B. M. Population-level effects of suppressing fever. Proc. Biol. Sci. 281, 20132570 (2014).

    PubMed  PubMed Central  Google Scholar 

  4. 4

    Schulman, C. I. et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg. Infect. (Larchmt) 6, 369–375 (2005). References 3 and 4 show that treatment of fever using antipyretic drugs has a detrimental effect on patient outcome during infection.

    Google Scholar 

  5. 5

    Ryan, M. & Levy, M. M. Clinical review: fever in intensive care unit patients. Crit. Care 7, 221–225 (2003).

    PubMed  PubMed Central  Google Scholar 

  6. 6

    Kurosawa, S., Kobune, F., Okuyama, K. & Sugiura, A. Effects of antipyretics in rinderpest virus infection in rabbits. J. Infect. Dis. 155, 991–997 (1987).

    CAS  PubMed  Google Scholar 

  7. 7

    Liu, E. et al. Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R1372–R1383 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Romanovsky, A. A. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R37–R46 (2007).

    CAS  PubMed  Google Scholar 

  9. 9

    Romanovsky, A. A., Shido, O., Sakurada, S., Sugimoto, N. & Nagasaka, T. Endotoxin shock: thermoregulatory mechanisms. Am. J. Physiol. 270, R693–R703 (1996).

    CAS  PubMed  Google Scholar 

  10. 10

    Almeida, M. C., Steiner, A. A., Branco, L. G. & Romanovsky, A. A. Cold-seeking behavior as a thermoregulatory strategy in systemic inflammation. Eur. J. Neurosci. 23, 3359–3367 (2006).

    PubMed  Google Scholar 

  11. 11

    Launey, Y., Nesseler, N., Malledant, Y. & Seguin, P. Clinical review: fever in septic ICU patients—friend or foe? Crit. Care 15, 222 (2011).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Polderman, K. H. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 371, 1955–1969 (2008).

    PubMed  Google Scholar 

  13. 13

    Bernheim, H. A. & Kluger, M. J. Fever: effect of drug-induced antipyresis on survival. Science 193, 237–239 (1976).

    CAS  PubMed  Google Scholar 

  14. 14

    Vaughn, L. K., Bernheim, H. A. & Kluger, M. J. Fever in the lizard Dipsosaurus dorsalis. Nature 252, 473–474 (1974).

    CAS  PubMed  Google Scholar 

  15. 15

    Covert, J. B. & Reynolds, W. W. Survival value of fever in fish. Nature 267, 43–45 (1977).

    CAS  PubMed  Google Scholar 

  16. 16

    Reynolds, W. W., Casterlin, M. E. & Covert, J. B. Behavioural fever in teleost fishes. Nature 259, 41–42 (1976). References 13–16 reveal that ectothermic vertebrates (lizards and fish) develop fever through behavioural changes and that fever is associated with a survival benefit.

    CAS  PubMed  Google Scholar 

  17. 17

    Simone-Finstrom, M., Foo, B., Tarpy, D. R. & Starks, P. T. Impact of food availability, pathogen exposure, and genetic diversity on thermoregulation in honey bees (Apis mellifera). J. Insect Behav. 27, 527–539 (2014).

    Google Scholar 

  18. 18

    Blanford, S. & Thomas, M. B. Adult survival, maturation, and reproduction of the desert locust Schistocerca gregaria infected with the fungus Metarhizium anisopliae var acridum. J. Invertebr. Pathol. 78, 1–8 (2001).

    CAS  PubMed  Google Scholar 

  19. 19

    Mackowiak, P. A. Fever: blessing or curse? A unifying hypothesis. Ann. Intern. Med. 120, 1037–1040 (1994).

    CAS  PubMed  Google Scholar 

  20. 20

    Cabanac, M. Fever in the leech, Nephelopsis obscura (Annelida). J. Comp. Physiol. B 159, 281–285 (1989).

    Google Scholar 

  21. 21

    Yarwood, C. E. Heat of respiration of injured and diseased leaves. Phytopathology 43, 675–681 (1953).

    Google Scholar 

  22. 22

    Zhu, Y. et al. Regulation of thermogenesis in plants: the interaction of alternative oxidase and plant uncoupling mitochondrial protein. J. Integr. Plant Biol. 53, 7–13 (2011).

    CAS  PubMed  Google Scholar 

  23. 23

    Pockley, A. G., Calderwood, S. K. & Santoro, M. G. Prokaryotic and Eukaryotic Heat Shock Proteins in Infectious Disease (Springer, 2010).

    Google Scholar 

  24. 24

    Lwoff, A. From protozoa to bacteria and viruses. Fifty years with microbes (André Lwoff). Annu. Rev. Microbiol. 25, 1–26 (1971).

    CAS  PubMed  Google Scholar 

  25. 25

    Osawa, E. & Muschel, L. H. Studies relating to the serum resistance of certain Gram-negative bacteria. J. Exp. Med. 119, 41–51 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Hasday, J. D., Thompson, C. & Singh, I. S. Fever, immunity, and molecular adaptations. Compr. Physiol. 4, 109–148 (2014).

    PubMed  Google Scholar 

  27. 27

    Morrison, S. F., Madden, C. J. & Tupone, D. Central control of brown adipose tissue thermogenesis. Front. Endocrinol. 3, 00005 (2012).

    CAS  Google Scholar 

  28. 28

    Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515–528 (2010).

    CAS  Google Scholar 

  29. 29

    Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nature Rev. Mol. Cell Biol. 11, 545–555 (2010).

    CAS  Google Scholar 

  30. 30

    Saper, C. B., Romanovsky, A. A. & Scammell, T. E. Neural circuitry engaged by prostaglandins during the sickness syndrome. Nature Neurosci. 15, 1088–1095 (2012).

    CAS  PubMed  Google Scholar 

  31. 31

    Matsumura, K. et al. Brain endothelial cells express cyclooxygenase-2 during lipopolysaccharide-induced fever: light and electron microscopic immunocytochemical studies. J. Neurosci. 18, 6279–6289 (1998).

    CAS  PubMed  Google Scholar 

  32. 32

    Yamagata, K. et al. Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J. Neurosci. 21, 2669–2677 (2001).

    CAS  PubMed  Google Scholar 

  33. 33

    Engstrom, L. et al. Lipopolysaccharide-induced fever depends on prostaglandin E2 production specifically in brain endothelial cells. Endocrinology 153, 4849–4861 (2012).

    PubMed  Google Scholar 

  34. 34

    Blatteis, C. M., Li, S., Li, Z., Feleder, C. & Perlik, V. Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat. 76, 1–18 (2005).

    CAS  PubMed  Google Scholar 

  35. 35

    Steiner, A. A., Chakravarty, S., Rudaya, A. Y., Herkenham, M. & Romanovsky, A. A. Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 107, 4000–4002 (2006). References 34 and 35 show that expression and release of PGE2 from haematopoietic cells is required for the development of fever during LPS challenge.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Roth, J. & Blatteis, C. M. Mechanisms of fever production and lysis: lessons from experimental LPS fever. Compr. Physiol. 4, 1563–1604 (2014).

    PubMed  Google Scholar 

  37. 37

    Ivanov, A. I. & Romanovsky, A. A. Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front. Biosci. 9, 1977–1993 (2004).

    CAS  PubMed  Google Scholar 

  38. 38

    Furuyashiki, T. & Narumiya, S. Stress responses: the contribution of prostaglandin E2 and its receptors. Nature Rev. Endocrinol. 7, 163–175 (2011).

    CAS  Google Scholar 

  39. 39

    Engblom, D. et al. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nature Neurosci. 6, 1137–1138 (2003).

    CAS  PubMed  Google Scholar 

  40. 40

    Lazarus, M. et al. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nature Neurosci. 10, 1131–1133 (2007). References 39 and 40 demonstrate that responses involving EP3 prostaglandin receptors are required for the development of fever.

    CAS  PubMed  Google Scholar 

  41. 41

    Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nature Neurosci. 11, 62–71 (2008).

    CAS  PubMed  Google Scholar 

  42. 42

    Dantzer, R. & Wollman, E. Molecular mechanisms of fever: the missing links. Eur. Cytokine Netw. 9, 27–31 (1998).

    CAS  PubMed  Google Scholar 

  43. 43

    Steinman, L. Nuanced roles of cytokines in three major human brain disorders. J. Clin. Invest. 118, 3557–3563 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004).

    CAS  Google Scholar 

  45. 45

    O'Neill, L. A., Golenbock, D. & Bowie, A. G. The history of Toll-like receptors — redefining innate immunity. Nature Rev. Immunol. 13, 453–460 (2013).

    CAS  Google Scholar 

  46. 46

    Elander, L., Ruud, J., Korotkova, M., Jakobsson, P. J. & Blomqvist, A. Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide. Neurosci. Lett. 470, 10–12 (2010).

    CAS  PubMed  Google Scholar 

  47. 47

    Hanada, R. et al. Central control of fever and female body temperature by RANKL/RANK. Nature 462, 505–509 (2009). This study identifies a pivotal role for RANKL in the brain in generating a fever in response to LPS.

    CAS  PubMed  Google Scholar 

  48. 48

    Benveniste, E. N., Sparacio, S. M., Norris, J. G., Grenett, H. E. & Fuller, G. M. Induction and regulation of interleukin-6 gene expression in rat astrocytes. J. Neuroimmunol. 30, 201–212 (1990).

    CAS  PubMed  Google Scholar 

  49. 49

    Beurel, E. & Jope, R. S. Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J. Neuroinflamm. 6, 9 (2009).

    Google Scholar 

  50. 50

    Sawada, M., Suzumura, A. & Marunouchi, T. TNFα induces IL-6 production by astrocytes but not by microglia. Brain Res. 583, 296–299 (1992).

    CAS  PubMed  Google Scholar 

  51. 51

    Woodroofe, M. N. et al. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J. Neuroimmunol. 33, 227–236 (1991).

    CAS  PubMed  Google Scholar 

  52. 52

    Ringheim, G. E., Burgher, K. L. & Heroux, J. A. Interleukin-6 mRNA expression by cortical neurons in culture: evidence for neuronal sources of interleukin-6 production in the brain. J. Neuroimmunol. 63, 113–123 (1995).

    CAS  PubMed  Google Scholar 

  53. 53

    Vallieres, L. & Rivest, S. Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1β. J. Neurochem. 69, 1668–1683 (1997).

    CAS  PubMed  Google Scholar 

  54. 54

    Cartmell, T., Poole, S., Turnbull, A. V., Rothwell, N. J. & Luheshi, G. N. Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J. Physiol. 526, 653–661 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Chai, Z., Gatti, S., Toniatti, C., Poli, V. & Bartfai, T. Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1β: a study on IL-6-deficient mice. J. Exp. Med. 183, 311–316 (1996).

    CAS  PubMed  Google Scholar 

  56. 56

    Kozak, W. et al. IL-6 and IL-1β in fever. Studies using cytokine-deficient (knockout) mice. Ann. NY Acad. Sci. 856, 33–47 (1998).

    CAS  PubMed  Google Scholar 

  57. 57

    Hamzic, N. et al. Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response. Brain Behav. Immun. 33, 123–130 (2013). References 55–57 highlight that loss of IL-6 signalling alone abrogates fever in response in LPS- or IL-1-induced inflammatory models.

    CAS  PubMed  Google Scholar 

  58. 58

    Nilsberth, C., Hamzic, N., Norell, M. & Blomqvist, A. Peripheral lipopolysaccharide administration induces cytokine mRNA expression in the viscera and brain of fever-refractory mice lacking microsomal prostaglandin E synthase-1. J. Neuroendocrinol. 21, 715–721 (2009).

    CAS  PubMed  Google Scholar 

  59. 59

    Jiang, Q. et al. Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice. Am. J. Physiol. 276, R1653–R1660 (1999).

    CAS  PubMed  Google Scholar 

  60. 60

    Ostberg, J. R., Taylor, S. L., Baumann, H. & Repasky, E. A. Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response. J. Leukoc. Biol. 68, 815–820 (2000).

    CAS  PubMed  Google Scholar 

  61. 61

    Rice, P. et al. Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia. J. Immunol. 174, 3676–3685 (2005). This report establishes that febrile temperatures drive CXCL8 expression to initiate neutrophil infiltration in the lungs.

    CAS  PubMed  Google Scholar 

  62. 62

    Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Teachey, D. T. et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121, 5154–5157 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Cao, C., Matsumura, K., Yamagata, K. & Watanabe, Y. Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1β: a possible site of prostaglandin synthesis responsible for fever. Brain Res. 733, 263–272 (1996).

    CAS  PubMed  Google Scholar 

  65. 65

    Konsman, J. P., Vigues, S., Mackerlova, L., Bristow, A. & Blomqvist, A. Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J. Comp. Neurol. 472, 113–129 (2004).

    PubMed  Google Scholar 

  66. 66

    Rummel, C., Sachot, C., Poole, S. & Luheshi, G. N. Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1316–R1326 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Turnbull, A. V., Prehar, S., Kennedy, A. R., Little, R. A. & Hopkins, S. J. Interleukin-6 is an afferent signal to the hypothalamo-pituitary-adrenal axis during local inflammation in mice. Endocrinology 144, 1894–1906 (2003).

    CAS  PubMed  Google Scholar 

  68. 68

    Sundgren-Andersson, A. K., Ostlund, P. & Bartfai, T. IL-6 is essential in TNF-α-induced fever. Am. J. Physiol. 275, R2028–R2034 (1998).

    CAS  PubMed  Google Scholar 

  69. 69

    Li, S., Goorha, S., Ballou, L. R. & Blatteis, C. M. Intracerebroventricular interleukin-6, macrophage inflammatory protein-1β and IL-18: pyrogenic and PGE2-mediated? Brain Res. 992, 76–84 (2003).

    CAS  PubMed  Google Scholar 

  70. 70

    Nilsberth, C. et al. The role of interleukin-6 in lipopolysaccharide-induced fever by mechanisms independent of prostaglandin E2 . Endocrinology 150, 1850–1860 (2009).

    CAS  PubMed  Google Scholar 

  71. 71

    Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    CAS  PubMed  Google Scholar 

  72. 72

    Hashizume, M. & Mihara, M. The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011, 765624 (2011).

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Soehnlein, O. & Lindbom, L. Phagocyte partnership during the onset and resolution of inflammation. Nature Rev. Immunol. 10, 427–439 (2010).

    CAS  Google Scholar 

  74. 74

    Girard, J. P., Moussion, C. & Forster, R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Rev. Immunol. 12, 762–773 (2012).

    CAS  Google Scholar 

  75. 75

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

    CAS  Google Scholar 

  76. 76

    Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).

    CAS  PubMed  Google Scholar 

  77. 77

    Ostberg, J. R., Ertel, B. R. & Lanphere, J. A. An important role for granulocytes in the thermal regulation of colon tumor growth. Immunol. Invest. 34, 259–272 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Takada, Y. et al. Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia. Int. J. Hyperthermia 16, 275–286 (2000).

    CAS  PubMed  Google Scholar 

  79. 79

    Bernheim, H. A., Bodel, P. T., Askenase, P. W. & Atkins, E. Effects of fever on host defense mechanisms after infection in the lizard Dipsosaurus dorsalis. Br. J. Exp. Pathol. 59, 76–84 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Ellis, G. S. et al. G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia. J. Appl. Physiol. 98, 1799–1804 (2005).

    CAS  PubMed  Google Scholar 

  81. 81

    Hasday, J. D. et al. Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity. Am. J. Pathol. 162, 2005–2017 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Capitano, M. L. et al. Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1-, IL-17-, and G-CSF-dependent manner. Blood 120, 2600–2609 (2012). This study demonstrates that fever-range hyperthermia promotes neutrophil release from the bone marrow and is protective following irradiation-induced neutropenia in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Ostberg, J. R. & Repasky, E. A. Comparison of the effects of two different whole body hyperthermia protocols on the distribution of murine leukocyte populations. Int. J. Hyperthermia 16, 29–43 (2000).

    CAS  PubMed  Google Scholar 

  84. 84

    Tulapurkar, M. E. et al. Febrile-range hyperthermia modifies endothelial and neutrophilic functions to promote extravasation. Am. J. Respir. Cell. Mol. Biol. 46, 807–814 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Singh, I. S. et al. Heat shock co-activates interleukin-8 transcription. Am. J. Respir. Cell Mol. Biol. 39, 235–242 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Zanker, K. S. & Lange, J. Whole body hyperthermia and natural killer cell activity. Lancet 1, 1079–1080 (1982).

    CAS  PubMed  Google Scholar 

  87. 87

    Shen, R. N., Hornback, N. B., Shidnia, H., Shupe, R. E. & Brahmi, Z. Whole-body hyperthermia decreases lung metastases in lung tumor-bearing mice, possibly via a mechanism involving natural killer cells. J. Clin. Immunol. 7, 246–253 (1987).

    CAS  PubMed  Google Scholar 

  88. 88

    Burd, R. et al. Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever-like) whole body hyperthermia. J. Cell. Physiol. 177, 137–147 (1998).

    CAS  PubMed  Google Scholar 

  89. 89

    Kappel, M., Stadeager, C., Tvede, N., Galbo, H. & Pedersen, B. K. Effects of in vivo hyperthermia on natural killer cell activity, in vitro proliferative responses and blood mononuclear cell subpopulations. Clin. Exp. Immunol. 84, 175–180 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Ostberg, J. R., Dayanc, B. E., Yuan, M., Oflazoglu, E. & Repasky, E. A. Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells. J. Leukoc. Biol. 82, 1322–1331 (2007).

    CAS  PubMed  Google Scholar 

  91. 91

    Multhoff, G., Botzler, C., Wiesnet, M., Eissner, G. & Issels, R. CD3− large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells. Blood 86, 1374–1382 (1995).

    CAS  PubMed  Google Scholar 

  92. 92

    Shi, H. et al. Hyperthermia enhances CTL cross-priming. J. Immunol. 176, 2134–2141 (2006).

    CAS  PubMed  Google Scholar 

  93. 93

    Jiang, Q. et al. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect. Immun. 68, 1265–1270 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

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

    CAS  PubMed  Google Scholar 

  95. 95

    Lee, C. T., Zhong, L., Mace, T. A. & Repasky, E. A. Elevation in body temperature to fever range enhances and prolongs subsequent responsiveness of macrophages to endotoxin challenge. PLoS ONE 7, e30077 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Lee, C. T. & Repasky, E. A. Opposing roles for heat and heat shock proteins in macrophage functions during inflammation: a function of cell activation state? Front. Immunol. 3, 140 (2012).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Pritchard, M. T., Li, Z. & Repasky, E. A. Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages. J. Leukoc. Biol. 78, 630–638 (2005).

    CAS  PubMed  Google Scholar 

  98. 98

    Gupta, A. et al. Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. J. Biol. Chem. 288, 2756–2766 (2013).

    CAS  PubMed  Google Scholar 

  99. 99

    Multhoff, G. Heat shock protein 70 (Hsp70): membrane location, export and immunological relevance. Methods 43, 229–237 (2007).

    CAS  PubMed  Google Scholar 

  100. 100

    Vega, V. L. et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J. Immunol. 180, 4299–4307 (2008).

    CAS  PubMed  Google Scholar 

  101. 101

    Noessner, E. et al. Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. J. Immunol. 169, 5424–5432 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Basu, S., Binder, R. J., Ramalingam, T. & Srivastava, P. K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14, 303–313 (2001).

    CAS  PubMed  Google Scholar 

  103. 103

    Binder, R. J. & Srivastava, P. K. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc. Natl Acad. Sci. USA 101, 6128–6133 (2004).

    CAS  PubMed  Google Scholar 

  104. 104

    Berwin, B. et al. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J. 22, 6127–6136 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Becker, T., Hartl, F. U. & Wieland, F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J. Cell Biol. 158, 1277–1285 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Arnouk, H. et al. Tumour secreted grp170 chaperones full-length protein substrates and induces an adaptive anti-tumour immune response in vivo. Int. J. Hyperthermia 26, 366–375 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Asea, A. et al. Novel signal transduction pathway utilized by extracellular HSP70: role of Toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277, 15028–15034 (2002).

    CAS  PubMed  Google Scholar 

  108. 108

    Facciponte, J. G., Wang, X. Y. & Subjeck, J. R. Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor-A and scavenger receptor expressed by endothelial cells-I. Eur. J. Immunol. 37, 2268–2279 (2007).

    CAS  PubMed  Google Scholar 

  109. 109

    Lehner, T. et al. Heat shock proteins generate β-chemokines which function as innate adjuvants enhancing adaptive immunity. Eur. J. Immunol. 30, 594–603 (2000).

    CAS  PubMed  Google Scholar 

  110. 110

    Panjwani, N. N., Popova, L. & Srivastava, P. K. Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J. Immunol. 168, 2997–3003 (2002).

    CAS  PubMed  Google Scholar 

  111. 111

    Snyder, Y. M., Guthrie, L., Evans, G. F. & Zuckerman, S. H. Transcriptional inhibition of endotoxin-induced monokine synthesis following heat shock in murine peritoneal macrophages. J. Leukoc. Biol. 51, 181–187 (1992).

    CAS  PubMed  Google Scholar 

  112. 112

    Yenari, M. A. et al. Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Ann. NY Acad. Sci. 1053, 74–83 (2005).

    CAS  PubMed  Google Scholar 

  113. 113

    Chen, H. et al. Hsp70 inhibits lipopolysaccharide-induced NF-κB activation by interacting with TRAF6 and inhibiting its ubiquitination. FEBS Lett. 580, 3145–3152 (2006).

    CAS  PubMed  Google Scholar 

  114. 114

    Schmitt, E., Gehrmann, M., Brunet, M., Multhoff, G. & Garrido, C. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J. Leukoc. Biol. 81, 15–27 (2007).

    CAS  PubMed  Google Scholar 

  115. 115

    Manzella, J. P. & Roberts, N. J. Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J. Immunol. 123, 1940–1944 (1979).

    CAS  PubMed  Google Scholar 

  116. 116

    Postic, B., DeAngelis, C., Breinig, M. K. & Monto, H. O. Effect of temperature on the induction of interferons by endotoxin and virus. J. Bacteriol. 91, 1277–1281 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Knippertz, I. et al. Mild hyperthermia enhances human monocyte-derived dendritic cell functions and offers potential for applications in vaccination strategies. Int. J. Hyperthermia 27, 591–603 (2011).

    CAS  PubMed  Google Scholar 

  118. 118

    van Bruggen, I., Robertson, T. A. & Papadimitriou, J. M. The effect of mild hyperthermia on the morphology and function of murine resident peritoneal macrophages. Exp. Mol. Pathol. 55, 119–134 (1991).

    CAS  PubMed  Google Scholar 

  119. 119

    Bachleitner-Hofmann, T. et al. Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 91, 4571–4577 (2006).

    CAS  PubMed  Google Scholar 

  120. 120

    Yan, X. et al. Fever range temperature promotes TLR4 expression and signaling in dendritic cells. Life Sci. 80, 307–313 (2007).

    CAS  PubMed  Google Scholar 

  121. 121

    Hatzfeld-Charbonnier, A. S. et al. Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J. Leukoc. Biol. 81, 1179–1187 (2007). This reference shows that the exposure of human monocyte-derived DCs to febrile temperatures improves their migratory response to chemokines in vitro and their ability to stimulate naive T cell activation.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Ostberg, J. R., Kaplan, K. C. & Repasky, E. A. Induction of stress proteins in a panel of mouse tissues by fever-range whole body hyperthermia. Int. J. Hyperthermia 18, 552–562 (2002).

    CAS  PubMed  Google Scholar 

  123. 123

    Peng, J. C. et al. Monocyte-derived DC primed with TLR agonists secrete IL-12p70 in a CD40-dependent manner under hyperthermic conditions. J. Immunother. 29, 606–615 (2006).

    CAS  PubMed  Google Scholar 

  124. 124

    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  PubMed  Google Scholar 

  125. 125

    Tal, O. et al. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J. Exp. Med. 208, 2141–2153 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Schumann, K. et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity 32, 703–713 (2010).

    CAS  PubMed  Google Scholar 

  127. 127

    Weber, M. et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339, 328–332 (2013).

    CAS  PubMed  Google Scholar 

  128. 128

    Ulvmar, M. H. et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nature Immunol. 15, 623–630 (2014). References 125–128 describe the role of CCR7 in sensing CCL21 gradients that direct the migration of mature DCs into the afferent lymphatics and within draining lymph nodes.

    CAS  Google Scholar 

  129. 129

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

    CAS  PubMed  Google Scholar 

  130. 130

    Blattman, J. N. et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J. Exp. Med. 195, 657–664 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Pabst, R. & Binns, R. M. Heterogeneity of lymphocyte homing physiology: several mechanisms operate in the control of migration to lymphoid and non-lymphoid organs in vivo. Immunol. Rev. 108, 83–109 (1989).

    CAS  PubMed  Google Scholar 

  132. 132

    Vardam, T. D. et al. Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. Cytokine 39, 84–96 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Boscacci, R. T. et al. Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing. Blood 116, 915–925 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    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 

  135. 135

    Evans, S. S. et al. Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix. J. Immunol. 162, 3615–3624 (1999).

    CAS  PubMed  Google Scholar 

  136. 136

    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  PubMed  Google Scholar 

  137. 137

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

    CAS  PubMed  Google Scholar 

  138. 138

    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  PubMed  Google Scholar 

  139. 139

    Appenheimer, M. M. et al. Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress. Eur. J. Immunol. 37, 2856–2867 (2007). References 138 and 139 identify an evolutionarily conserved role of IL-6 trans -signalling in enhancing L-selectin-dependent adhesion in lymphocytes during exposure to febrile temperatures.

    CAS  PubMed  Google Scholar 

  140. 140

    Chen, Q. et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nature Immunol. 7, 1299–1308 (2006). This study establishes that fever-range thermal stress acts through an IL-6 trans -signalling-dependent mechanism to upregulate ICAM1 expression selectively in HEVs.

    CAS  Google Scholar 

  141. 141

    Chen, Q. et al. Thermal facilitation of lymphocyte trafficking involves temporal induction of intravascular ICAM-1. Microcirculation 16, 143–158 (2009). This study reveals the restricted temporal nature of ICAM1 induction on HEV in response to fever-range hyperthermia and that restoration of normal trafficking involves a zinc-dependent metalloproteinase-dependent mechanism.

    PubMed  Google Scholar 

  142. 142

    Fisher, D. T. et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J. Clin. Invest. 121, 3846–3859 (2011). This study demonstrates that febrile-range thermal therapy acts through IL-6 trans -signalling to promote the trafficking of CD8+ effector T cells into the tumour microenvironment and delays tumour growth.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Kraybill, W. G. et al. A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models. Int. J. Hyperthermia 18, 253–266 (2002).

    CAS  PubMed  Google Scholar 

  144. 144

    Picker, L. J. & Butcher, E. C. Physiological and molecular mechanisms of lymphocyte homing. Annu. Rev. Immunol. 10, 561–591 (1992).

    CAS  PubMed  Google Scholar 

  145. 145

    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  PubMed  Google Scholar 

  146. 146

    Schurpf, T. & Springer, T. A. Regulation of integrin affinity on cell surfaces. EMBO J. 30, 4712–4727 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    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  PubMed  PubMed Central  Google Scholar 

  148. 148

    Carman, C. V. & Springer, T. A. Trans-cellular migration: cell–cell contacts get intimate. Curr. Opin. Cell Biol. 20, 533–540 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Roberts, N. J. Jr & Steigbigel, R. T. Hyperthermia and human leukocyte functions: effects on response of lymphocytes to mitogen and antigen and bactericidal capacity of monocytes and neutrophils. Infect. Immun. 18, 673–679 (1977).

    PubMed  PubMed Central  Google Scholar 

  150. 150

    Smith, J. B., Knowlton, R. P. & Agarwal, S. S. Human lymphocyte responses are enhanced by culture at 40 °C. J. Immunol. 121, 691–694 (1978).

    CAS  PubMed  Google Scholar 

  151. 151

    Mace, T. A. et al. Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia. J. Leukoc. Biol. 90, 951–962 (2011). This study shows that fever-range temperatures enhance T cell activation by altering the fluidity of the plasma membrane and by pre-association of the signalling components of the TCR complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Mace, T. A., Zhong, L., Kokolus, K. M. & Repasky, E. A. Effector CD8+ T cell IFN-γ production and cytotoxicity are enhanced by mild hyperthermia. Int. J. Hyperthermia 28, 9–18 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Zynda, E. et al. A role for the thermal microenvironment in co-stimulation requirements during T cell activation. Cell Cycle (in the press).

  154. 154

    Calabrese, L. H. & Rose-John, S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nature Rev. Rheumatol. 10, 720–727 (2014).

    CAS  Google Scholar 

  155. 155

    Fisher, D. T., Appenheimer, M. M. & Evans, S. S. The two faces of IL-6 in the tumor microenvironment. Semin. Immunol. 26, 38–47 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Jostock, T. et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur. J. Biochem. 268, 160–167 (2001).

    CAS  PubMed  Google Scholar 

  157. 157

    Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nature Med. 6, 583–588 (2000).

    CAS  PubMed  Google Scholar 

  158. 158

    Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Rev. Cancer 9, 798–809 (2009).

    CAS  Google Scholar 

  159. 159

    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  PubMed  Google Scholar 

  160. 160

    Lefor, A. T. et al. Hyperthermia increases intercellular adhesion molecule-1 expression and lymphocyte adhesion to endothelial cells. Surgery 116, 214–220; discussion 220–221 (1994).

    CAS  PubMed  Google Scholar 

  161. 161

    Ager, A. Isolation and culture of high endothelial cells from rat lymph nodes. J. Cell Sci. 87, 133–144 (1987).

    PubMed  Google Scholar 

  162. 162

    Lee, M. et al. Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nature Immunol. 15, 982–995 (2014).

    CAS  Google Scholar 

  163. 163

    Mikucki, M. E. et al. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int. J. Hyperthermia 29, 464–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Malhotra, D. et al. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nature Immunol. 13, 499–510 (2012).

    CAS  Google Scholar 

  165. 165

    Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J. Exp. Med. 200, 783–795 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Inouye, S. et al. Heat shock transcription factor 1 opens chromatin structure of interleukin-6 promoter to facilitate binding of an activator or a repressor. J. Biol. Chem. 282, 33210–33217 (2007).

    CAS  PubMed  Google Scholar 

  167. 167

    House, S. D. et al. Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response. Cell Stress Chaperones 6, 164–171 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Ensor, J. E. et al. Differential effects of hyperthermia on macrophage interleukin-6 and tumor necrosis factor-α expression. Am. J. Physiol. 266, C967–C974 (1994).

    CAS  PubMed  Google Scholar 

  169. 169

    Fairchild, K. D., Viscardi, R. M., Hester, L., Singh, I. S. & Hasday, J. D. Effects of hypothermia and hyperthermia on cytokine production by cultured human mononuclear phagocytes from adults and newborns. J. Interferon Cytokine Res. 20, 1049–1055 (2000).

    CAS  PubMed  Google Scholar 

  170. 170

    Hagiwara, S., Iwasaka, H., Matsumoto, S. & Noguchi, T. Changes in cell culture temperature alter release of inflammatory mediators in murine macrophagic RAW264.7 cells. Inflamm. Res. 56, 297–303 (2007).

    CAS  PubMed  Google Scholar 

  171. 171

    Cooper, Z. A. et al. Febrile-range temperature modifies cytokine gene expression in LPS-stimulated macrophages by differentially modifying NF-κB recruitment to cytokine gene promoters. Am. J. Physiol. Cell Physiol. 298, C171–C181 (2010).

    CAS  PubMed  Google Scholar 

  172. 172

    Ensor, J. E., Crawford, E. K. & Hasday, J. D. Warming macrophages to febrile range destabilizes tumor necrosis factor-α mRNA without inducing heat shock. Am. J. Physiol. 269, C1140–C1146 (1995).

    CAS  PubMed  Google Scholar 

  173. 173

    Singh, I. S., He, J. R., Calderwood, S. & Hasday, J. D. A high affinity HSF-1 binding site in the 5′-untranslated region of the murine tumor necrosis factor-α gene is a transcriptional repressor. J. Biol. Chem. 277, 4981–4988 (2002).

    CAS  PubMed  Google Scholar 

  174. 174

    Fiuza, C. et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101, 2652–2660 (2003).

    CAS  PubMed  Google Scholar 

  175. 175

    Lee, C. T. et al. Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis. PLoS ONE 10, e0120327 (2015).

    PubMed  PubMed Central  Google Scholar 

  176. 176

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  PubMed  Google Scholar 

  177. 177

    Cannon, B. & Nedergaard, J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J. Exp. Biol. 214, 242–253 (2011).

    PubMed  Google Scholar 

  178. 178

    Elenkov, I. J., Wilder, R. L., Chrousos, G. P. & Vizi, E. S. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595–638 (2000).

    CAS  PubMed  Google Scholar 

  179. 179

    Eng, J. W. et al. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol. Immunother. 63, 1115–1128 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Padgett, D. A. & Glaser, R. How stress influences the immune response. Trends Immunol. 24, 444–448 (2003).

    CAS  PubMed  Google Scholar 

  181. 181

    Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211, 2583–2598 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Slota, C., Shi, A., Chen, G., Bevans, M. & Weng, N. P. Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation. Brain Behav. Immun. 46, 168–179 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Kokolus, K. M. et al. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc. Natl Acad. Sci. USA 110, 20176–20181 (2013). References 183 and 184 establish that noradrenaline-driven thermogenesis shapes the phenotype of the immune response by altering macrophage differentiation and antitumour immunity.

    CAS  PubMed  Google Scholar 

  185. 185

    Kokolus, K. M. et al. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naive and tumor-bearing mice. Front. Immunol. 5, 23 (2014).

    PubMed  PubMed Central  Google Scholar 

  186. 186

    Eng, J. W. et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation. Nature Commun. 6, 6426 (2015).

    CAS  Google Scholar 

  187. 187

    Glaser, R. & Kiecolt-Glaser, J. K. Stress-induced immune dysfunction: implications for health. Nature Rev. Immunol. 5, 243–251 (2005).

    CAS  Google Scholar 

  188. 188

    Karp, C. L. & Murray, P. J. Non-canonical alternatives: what a macrophage is 4. J. Exp. Med. 209, 427–431 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Di, Y. P., Repasky, E. A. & Subjeck, J. R. Distribution of HSP70, protein kinase C, and spectrin is altered in lymphocytes during a fever-like hyperthermia exposure. J. Cell. Physiol. 172, 44–54 (1997).

    CAS  PubMed  Google Scholar 

  190. 190

    Tulapurkar, M. E., Asiegbu, B. E., Singh, I. S. & Hasday, J. D. Hyperthermia in the febrile range induces HSP72 expression proportional to exposure temperature but not to HSF-1 DNA-binding activity in human lung epithelial A549 cells. Cell Stress Chaperones 14, 499–508 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Gothard, L. Q., Ruffner, M. E., Woodward, J. G., Park-Sarge, O. K. & Sarge, K. D. Lowered temperature set point for activation of the cellular stress response in T-lymphocytes. J. Biol. Chem. 278, 9322–9326 (2003).

    CAS  PubMed  Google Scholar 

  192. 192

    Rossi, A., Coccia, M., Trotta, E., Angelini, M. & Santoro, M. G. Regulation of cyclooxygenase-2 expression by heat: a novel aspect of heat shock factor 1 function in human cells. PLoS ONE 7, e31304 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Chatterjee, M. et al. STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90α and β in multiple myeloma cells, which critically contribute to tumor-cell survival. Blood 109, 720–728 (2007).

    CAS  PubMed  Google Scholar 

  194. 194

    Marubayashi, S. et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J. Clin. Invest. 120, 3578–3593 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Sato, N. et al. Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3. Biochem. Biophys. Res. Commun. 300, 847–852 (2003).

    CAS  PubMed  Google Scholar 

  196. 196

    Shang, L. & Tomasi, T. B. The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons. J. Biol. Chem. 281, 1876–1884 (2006).

    CAS  PubMed  Google Scholar 

  197. 197

    Weigert, O. et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J. Exp. Med. 209, 259–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Patapoutian, A., Peier, A. M., Story, G. M. & Viswanath, V. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nature Rev. Neurosci. 4, 529–539 (2003).

    CAS  Google Scholar 

  199. 199

    Ramsey, I. S., Delling, M. & Clapham, D. E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006).

    CAS  PubMed  Google Scholar 

  200. 200

    Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nature Rev. Cancer 10, 537–549 (2010).

    CAS  Google Scholar 

  201. 201

    Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).

    CAS  PubMed  Google Scholar 

  202. 202

    Ahn, S. G. & Thiele, D. J. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev. 17, 516–528 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005).

    CAS  Google Scholar 

  204. 204

    Neckers, L. & Workman, P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin. Cancer Res. 18, 64–76 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Muralidharan, S. & Mandrekar, P. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J. Leukoc. Biol. 94, 1167–1184 (2013).

    PubMed  PubMed Central  Google Scholar 

  206. 206

    Chu, K. F. & Dupuy, D. E. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nature Rev. Cancer 14, 199–208 (2014).

    CAS  Google Scholar 

  207. 207

    Repasky, E. A., Evans, S. S. & Dewhirst, M. W. Temperature matters! And why it should matter to tumor immunologists. Cancer Immunol. Res. 1, 210–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Haemmerich, D. & Laeseke, P. F. Thermal tumour ablation: devices, clinical applications and future directions. Int. J. Hyperthermia 21, 755–760 (2005).

    CAS  PubMed  Google Scholar 

  209. 209

    Issels, R. D. et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 11, 561–570 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Wessalowski, R. et al. Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol. 14, 843–852 (2013).

    PubMed  Google Scholar 

  211. 211

    Jones, E. L. et al. Randomized trial of hyperthermia and radiation for superficial tumors. J. Clin. Oncol. 23, 3079–3085 (2005). References 209–211 demonstrate that thermal therapy has a clinical benefit when used in an adjuvant setting in combination with chemotherapy or radiotherapy.

    PubMed  Google Scholar 

  212. 212

    Kong, G., Braun, R. D. & Dewhirst, M. W. Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature. Cancer Res. 61, 3027–3032 (2001).

    CAS  PubMed  Google Scholar 

  213. 213

    Sen, A. et al. Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res. 71, 3872–3880 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Xu, Y. et al. Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin. Int. J. Hyperthermia 23, 513–527 (2007).

    CAS  PubMed  Google Scholar 

  215. 215

    Song, C. W., Park, H. J., Lee, C. K. & Griffin, R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int. J. Hyperthermia 21, 761–767 (2005).

    CAS  PubMed  Google Scholar 

  216. 216

    Dewhirst, M. W., Landon, C. D., Hofmann, C. L. & Stauffer, P. R. Novel approaches to treatment of hepatocellular carcinoma and hepatic metastases using thermal ablation and thermosensitive liposomes. Surg. Oncol. Clin. N. Am. 22, 545–561 (2013).

    PubMed  PubMed Central  Google Scholar 

  217. 217

    Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. & Wolchok, J. D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185–202 (2014).

    CAS  PubMed  Google Scholar 

  218. 218

    Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature Rev. Immunol. 12, 269–281 (2012).

    CAS  Google Scholar 

  219. 219

    Palucka, K. & Banchereau, J. Cancer immunotherapy via dendritic cells. Nature Rev. Cancer 12, 265–277 (2012).

    CAS  Google Scholar 

  220. 220

    Wolchok, J. D. & Chan, T. A. Cancer: antitumour immunity gets a boost. Nature 515, 496–498 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Guo, J. et al. Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma. Int. J. Cancer 120, 2418–2425 (2007).

    CAS  PubMed  Google Scholar 

  222. 222

    Mukhopadhaya, A. et al. Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity. Cancer Res. 67, 7798–7806 (2007).

    CAS  PubMed  Google Scholar 

  223. 223

    Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank M. Appenheimer, J. Black and M. Messmer for helpful comments on the manuscript, and E. Smith and UC Berkeley Natural Resources Library for assistance with archived citations. This work was supported by the US National Institutes of Health (CA79765, CA085183 and AI082039) and the Jennifer Linscott Tietgen Family Foundation. The authors also acknowledge the significant contributions of colleagues in the field that could not always be cited owing to space limitations.

Author information

Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, 14263, New York, USA

    Sharon S. Evans, Elizabeth A. Repasky & Daniel T. Fisher

Authors
  1. Sharon S. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth A. Repasky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel T. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharon S. Evans.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Evans, S., Repasky, E. & Fisher, D. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 15, 335–349 (2015). https://doi.org/10.1038/nri3843

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing