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Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human beta-defensins are also chemotactic for immature dendritic cells and memory T cells. Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by beta-defensin. Thus, beta-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.
Defensins, a family of small (3.5 to 4.5 kD) cationic antimicrobial peptides with three to four intramolecular cysteine disulfide bonds, are found in mammals, insects, and plants (1-4). On the basis of the position and bonding of six conserved cysteine residues, defensins in vertebrates are divided into two categories, designated as a- and Beta-defensins (1, 2). Unlike a-defensins that are produced by neutrophils and intestinal Paneth cells, Beta-defensins are primarily expressed by epithelial cells of the skin, kidneys, and tracheabronchial lining of nearly all vertebrates, where they can be released upon microbial invasion or up-regulated by stimulation with lipopolysaccharide and tumor necrosis factor-alpha (TNF-alpha) (2, S, 6). Two types of human Beta-defensins (HBDs) beta-defensins 1 and 2 (HBD1 and HBD2, respectively), have been identified (6> 7). Inactivation of the antimicrobial activity of HBDs is reported to contribute to the recurrent airway infections in patients with cystic fibrosis (8> 9).
The alpha-defensins may also have roles in protecting the host, based on their capacity to chemoattract T cells (10), to promote host immunity (II), and to activate the classical complement pathway (11). Because Beta-defensins are released upon microbial invasion and are located at the host-environment interface, such as mucosal surfaces and skin (2, S, 6), they may also function to alert the adaptive immune system of vertebrates. We therefore investigated whether HBDs could chemotactically mobilize human dendritic cells (DCs), monocytes, and T cells (13, 14). Psoriatic skin-derived pure HBD2 (skin HBD2), synthetic HBD2 (sHBD2), and recombinant HBD2 (rHBD2), all induced substantial in vitro migration of CD34+ progenitor-derived DCs in a dose-dependent manner, with optimal concentrations...