Fever-range hyperthermia stimulates alpha 4 beta 7 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 stu dies have shown that L-selectin adhesion is dynamically regulated by febril e temperatures. It is now reported that fever-range hyperthermia also acts directly on lymphocytes to enhance selected adhesive functions of alpha 4 b eta 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 endothe lial venules (HEV) in Peyer's patch and mesenteric lymph node frozen sectio ns. TK1 cells are alpha 4 beta 7(hi) L-selectin(lo), allowing for the analy sis of alpha 4 beta 7 integrin without contributions from L-selectin. Adhes ion was further shown to involve alpha 4 beta 7 integrin and its endothelia l counter-receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) u sing function-blocking antibodies (i.e. DATK32, HP2/1, MECA-367). Fever-ran ge hyperthermia also promotes alpha 4 beta 7 integrin-mediated aggregation of TK1 cells, In sharp contrast, hyperthermia fails to increase alpha 4 bet a 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 hypertherm ia, suggesting that hyperthermia stimulates adhesion by enhancing alpha 4 b eta 7 integrin avidity rather than its cell surface density. These results provide a mechanism whereby febrile temperatures during infection or clinic al hyperthermia potentially amplify the immune response by stimulating L-se lectin and alpha 4 beta 7 integrin-dependent homing of immune effector cell s to lymphoid tissues.