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

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.

Primary immune surveillance: some like it hot

“…Lymphocyte aggregates were not detected in vivo, consistent with prior observations that heat treatment alone does not induce homotypic adhesion in lymphocytes in vitro [31]. To minimize the known nonspecific effects of thermal stress on hemodynamic parameters such as vasodilatation and increased blood flow [25,26,32], which could have an impact on lymphocyte-endothelial interactions during the observation period, heated mice were allowed to revert to normothermal core temperature before adoptive transfer of fluorescent-labeled lymphocytes. Given that the velocity of noninteracting lymphocytes passing through the venular tree was similar between normothermic and hyperthermia-pretreated groups, improved lymphocyteendothelial interactions were likely due to molecular changes in the endothelium and not from nonspecific hemodynamic thermal effects [25].…”

“…In vivo homing studies also demonstrated a twofold increase in trafficking of normothermic lymphocytes to PLNs, PPs, and MLNs in mice receiving WBH. Paralleling the results of frozen section adherence assays, heat effects on homing were site specific, supported by the lack of an increase in homing to sites with normal squamous endothelial vasculature such as the liver or pancreas [25,26,32].…”

“…Fever-range thermal stress has also been shown to act independently upon HEVs to increase their adhesive properties as observed in multiple murine strains [25,26]. In vitro Stamper-Woodruff assays using PLNs or PPs of mice treated with WBH (39.5±0.5°C for 6 h) demonstrated improved ability of HEVs to support lymphocyte adhesion compared to normothermic controls.…”

“…WBH also shortens the time to generate an immune response by stimulating the migration of skin-derived dendritic cells (i.e., Langerhans cells) to lymph nodes where they colocalize with arriving T lymphocytes [21,24]. Recently, lymphocyte recruitment to lymph nodes and PPs, a key component of primary immune surveillance, has been demonstrated to improve with the application of feverrange WBH [25,26].…”

“…Interactions between fluorescenttagged lymphocytes and vascular substrates in PLNs of living mice demonstrated a functional dichotomy between the effects of thermal stress on higher-order HEVs and lower-order venules [25]. Although the rolling interactions did not manifest any change, the number of lymphocytes achieving firm arrest increased with WBH and was restricted to the higher-order HEVs [25]. Lymphocyte aggregates were not detected in vivo, consistent with prior observations that heat treatment alone does not induce homotypic adhesion in lymphocytes in vitro [31].…”