Fever-range hyperthermia stimulates α4β7 integrin-dependent lymphocyte-endothelial adhesion

Migration of blood-borne lymphocytes into lymphoid tissues is initiated by the L-selectin and α4β7 integrin adhesion molecules. Previous studies have shown that L-selectin adhesion is dynamically regulated by febrile temperatures. It is now reported that fever-range hyperthermia also acts directly on lymphocytes to enhance selected adhesive functions of α4β7 integrin. Fever-range hyperthermia treatment in vitro (40°C, 12 h) of murine TK1 lymphoma cells and human peripheral blood lymphocytes (PBL) stimulates α4β7 integrin-dependent adhesion to high endothelial venules (HEV) in Peyer's patch and mesenteric lymph node frozen sections. TK1 cells are α4β7(hi) L-selectin(lo), allowing for the analysis of α4β7 integrin without contributions from L-selectin. Adhesion was further shown to involve α4β7 integrin and its endothelial counter-receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) using function-blocking antibodies (i.e. DATK32, HP2/1, MECA-367). Fever-range hyperthermia also promotes α4β7 integrin-mediated aggregation of TK1 cells. In sharp contrast, hyperthermia fails to increase α4β7 integrin adhesion to fibronectin by TK1 cells. Expression of the α4β7 heterodimer on TK1 cells or human PBL is not altered by hyperthermia, suggesting that hyperthermia stimulates adhesion by enhancing α4β7 integrin avidity rather than its cell surface density. These results provide a mechanism whereby febrile temperatures during infection or clinical hyperthermia potentially amplify the immune response by stimulating L-selectin and α4β7 integrin-dependent homing of immune effector cells to lymphoid tissues.