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 alpha 4 beta 7 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 alpha 4 beta 7 integrin. :Fever-range hyperthermia treatment in vitro (40 degrees C, 12 h) of murine TK1 lymphoma cells and human peripheral blood lymphocytes (PBL) stimulates alpha 4 beta 7 integrin-dependent adhesion to high endothelial venules (HEV) in Peyer's patch and mesenteric lymph node frozen sections. TK1 cells are alpha 4 beta 7(hi) L-selectin(lo), allowing for the analysis of alpha 4 beta 7 integrin without contributions from L-selectin. Adhesion was further shown to involve alpha 4 beta 7 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 alpha 4 beta 7 integrin-mediated aggregation of TK1 cells, In sharp contrast, hyperthermia fails to increase alpha 4 beta 7 integrin adhesion to fibronectin by TK1 cells. Expression of the alpha 4 beta 7 heterodimer on TK1 cells or human PBL is not altered by hyperthermia, suggesting that hyperthermia stimulates adhesion by enhancing alpha 4 beta 7 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 alpha 4 beta 7 integrin-dependent homing of immune effector cells to lymphoid tissues.