Thermal enhancement of immune surveillance depends on increased expression of trafficking molecules such as ICAM-1 on HEVs. This initial phase is dependent on IL-6. Following cessation of thermal stress, ICAM-1 expression and lymphocyte trafficking are restored to homeostatic levels by zinc-dependent sheddase activity. Membrane and soluble (s) forms of ICAM-1 are depicted.

The schematic depicts the biphasic nature of the inflammatory response triggered by inflammatory stimuli that accompany infection such as systemic fever. The initiation phase of acute inflammation is characterized by the rapid transition from steady-state homeostatic levels of lymphocyte trafficking across vascular endothelial barriers to elevated, peak levels of extravasation. Resolution of inflammation is dependent on the rapid restoration of lymphocyte trafficking to normal steady-state levels.

Fever-range thermal stress targets discrete molecular events in the multistep adhesion cascade that governs lymphocyte trafficking across high endothelial venules (HEVs). Molecules regulated by fever-range temperatures are indicated by red text in the schematic. Photomicrograph shown in lower panel depicts a typical PNAd⁺ HEV (indicated by green immunofluorescence stain) in a murine lymph node cryosections. Bar = 100 μm. Note the cuboidal morphology of the endothelial cells lining the HEV. The white dotted line demarks the boundary of the HEV.

Fever-range thermal stress dynamically regulates lymphocyte trafficking across HEVs of peripheral lymph nodes. Left panel depicts the homing of fluorescent-labeled (TRITC, red) naïve lymphocytes across cuboidal high endothelial venules (HEVs; demarked by white dotted line) was investigated in short-term (1 h) homing assays after intravenous injection of labeled lymphocytes. Lymph node cryosections were subsequently counterstained for the expression of ICAM-1 (green). Photomicrographs show the distribution of TRITC-labeled lymphocytes in ICAM-1⁺ HEVs in peripheral lymph nodes of mice treated with fever-range thermal stress (FRTS) or normothermal controls (NT). Bar = 10 μm. Note the relative increase in TRITC-labeled lymphocytes and ICAM-1 staining intensity in HEVs following thermal stress. Middle panels, histograms depict the immunofluorescence intensity of ICAM-1 staining quantified in all HEVs in a cross-section of lymph nodes by computer-assisted image analysis; the mean fluorescence intensity (MFI) is indicated for each condition. Right panels indicate the number of TRITC-labeled cells in lymph node cryosections detected by fluorescence microscopy (n = 10 fields). *p < 0.007 by Student’s t-test for difference between normothermal and fever-range thermal stress conditions.