The innate immune system responses rapidly to pathogens, either by obstruction and direct killing of microbes or by activation of the adaptive arm of the immune system. Defensins have feet in both camps, and two studies add insight into how they work (see the Perspective by Ganz). Although chemokines play a role in the inhibition of human immunodeficiency virus-type 1 (HIV-1) replication by CD8 T cells, the full identity of the factors involved has been elusive. Zhang et al. used mass spectrometry and protein chip technology to examine culture supernatants from CD8 T cells isolated from patients who are long-term nonprogressors to AIDS. On the basis of amino acid sequencing and antibody recognition, they identified a set of defensins that only appeared upon T cell activation. Antibodies to these molecules blocked viral inhibition by CD8, and commercial preparations of α-defensins 1 and 2 inhibited different HIV-1 isolates. Biragyn et al. find that one defensin, β-defensin 2, could activate dendritic cells (DCs) by binding Toll-like receptor-4 (TLR-4), a cell-surface pattern-recognition protein hitherto considered to be limited to recognizing pathogen-derived molecules, such as the Gram-negative bacterial endotoxin, lipopolysaccharide (LPS). In DCs, the interaction of β-defensin 2 with TLR-4 induced much the same cellular activation program as LPS, with the stimulation of costimulatory molecule and proinflammatory cytokine expression. T. Ganz, Versatile defensins. Science 298 , 977-979 (2002). [Summary] [Full Text] L. Zhang, W. Yu, T. He, J. Yu, R. E. Caffrey, E. A. Dalmasso, S. Fu, T. Pham, J. Mei, J. J. Ho, W. Zhang, P. Lopez, D. D. Ho, Contribution of human α-defensin-1, -2, and -3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 298 , 995-1000 (2002). [Abstract] [Full Text] A. Biragyn, P. A. Ruffini, C. A. Leifer, E. Klyushnenkova, A. Shakhov, O. Chertov, A. K. Shirakawa, J. M. Farber, D. M. Segal, J. J. Oppenheim, L. W. Kwak, Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science 298 , 1025-1029 (2002). [Abstract] [Full Text]