84 Ó 2011 John Wiley & Sons A/S • Immunological Reviews 245/2012 Robert I. Lehrer Wuyuan Lu a-Defensins in human innate immunity Authors’ addresses Robert I. Lehrer 1 , Wuyuan Lu 2 1 Department of Medicine and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 2 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA. Correspondence to: Robert I. Lehrer Department of Medicine David Geffen School of Medicine at UCLA 10833 LeConte Avenue Los Angeles, CA 90095-1688, USA Tel.: +1 310 825 5340 Fax: +1 310 206 8766 e-mail: rlehrer@mednet.ucla.edu Acknowledgements The authors declare no conflict of interest. This article is part of a series of reviews covering Microbial Influences on Immune Function appearing in Volume 245 of Immunological Reviews. Immunological Reviews 2012 Vol. 245: 84–112 Printed in Singapore. All rights reserved Ó 2011 John Wiley & Sons A/S Immunological Reviews 0105-2896 Summary: Defensins are small, multifunctional cationic peptides. They typically contain six conserved cysteines whose three intramolecular disulfides stabilize a largely b-sheet structure. This review of human a-defensins begins by describing their evolution, including their likely relationship to the Big Defensins of invertebrates, and their kinship to the b-defensin peptides of many if not all vertebrates, and the h-defensins found in certain non-human primates. We provide a short history of the search for leukocyte-derived microbicidal molecules, emphasizing the roles played by luck (good), preconceived notions (mostly bad), and proper timing (essential). The antimicrobial, antiviral, antitoxic, and binding properties of human a-defensins are summarized. The structural features of a-defensins are described extensively and their functional con- tributions are assessed. The properties of HD6, an enigmatic Paneth cell a-defensin, are contrasted with those of the four myeloid a-defensins (HNP1–4) and of HD5, the other a-defensin of human Paneth cells. The review ends with a decalogue that may assist researchers or students interested in a-defensins and related aspects of neutrophil function. Keywords: antimicrobial peptides, defensins, innate immunity, neutrophil, Paneth cells Evolution of defensins The defensins of vertebrate animals are small, cationic, and amphipathic peptides that contain 18–45 amino acid residues. They comprise three subfamilies, called a, b, and h-defensins. Each subfamily has a conserved motif that includes six cyste- ine residues that form three intramolecular disulfide bonds with a characteristic and different pattern of pairing. Addi- tional families of small, cysteine-rich antimicrobial peptides (AMPs) exist in plants (1), fungi (2), myxobacteria (3), and invertebrates (4, 5), including several that are also called de- fensins. Some fungal defensins display remarkable sequence homology to peptides found in invertebrates (6), and plant defensins are structurally similar to insect defensins and scor- pion toxins (7). At present, based on common structural and sequence features, only members of the ‘Big Defensin’ (BD) peptide family (8) seem likely to be genetic (and rather dis- tant) cousins of the defensins found in vertebrates. The first purified BD was isolated from the hemocytes (white blood cells) of a horseshoe crab, Tachypleus tridentatus