A longstanding question in immunology revolves around the physiological benefit of the ancient fever response. Despite the fact that fever occurs at great metabolic cost, it is associated with improved survival during infection in endothermic and ectothermic vertebrate species (1). The prevailing paradigm with regard to leukocyte trafficking has been that febrile temperatures influence leukocyte delivery to tissues principally through bystander effects on hemodynamic parameters (i.e., vasodilation and increased blood flow). This chapter focuses on emerging evidence for a proactive role of temperatures in the range of natural fever (i.e., 38–40°C) in regulating the molecular events that support lymphocyte adhesion in high-endothelial venules (HEVs). HEVs are major sites of lymphocyte extravasation, serving as a locus for recirculation of blood-borne lymphocytes through peripheral lymphoid organs. Continuous entry of naïve and central memory lymphocytes across HEVs is crucial for immune homeostasis and immune surveillance. Notably, the mechanisms by which fever-range thermal stress promote lymphocyte–endothelial interactions are tightly regulated with respect to the type of vessels involved. Sustained exposure to fever-range thermal stress selectively targets adhesion HEVs, whereas squamous endothelial cells (ECs) of noninflamed extralymphoid organs are not responsive. The physiological fever-range thermal stimulus described here is distinct from heat shock conditions (e.g., ≥43°C) that globally promote adhesion in nonactivated EC. These observations support the concept that HEVs act as sentinels during febrile inflammatory responses by heightening the delivery of naïve and central memory lymphocytes to secondary lymphoid organs.

OVERVIEW OF THE MOLECULAR MECHANISMS ORCHESTRATING LYMPHOCYTE TRAFFICKING ACROSS HIGH-ENDOTHELIAL VENULES

HEVs function as gatekeepers controlling the egress of lymphocytes out of the peripheral blood compartment and into secondary lymphoid organs where pathogens and cognate antigens are encountered (2–4).