Tuning Immune Stimulation

Abstract

During vaccination, an additional stimulus to the immune response is often needed and is provided by a material called an adjuvant. Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria is a potent stimulant of the innate immune response, but the potential for toxic shock does not allow for its use in humans. A recently approved adjuvant, monophosphoryl lipid A (MPLA), has limited side effects compared with LPS, from which it is derived (see the Perspective by Fitzgerald and Golenbock). Mata-Haro et al . show that MPLA activates only a specific signaling component of the Toll-like receptor 4 (TLR4) pathway and avoids the myeloid differentiation factor 88 arm of TLR4 signaling, which can account for the much higher toxicity associated with LPS. Ohto et al . determined crystal structures of the TLR4 co-receptor MD-2 alone and in complex with the antiendotoxic tetra-acylated lipid A core of LPS. MD-2 has a deep hydrophobic cavity that accommodates the four acyl chains of the lipid core. V. Mata-Haro, C. Cekic, M. Martin, P. M. Chilton, C. R. Casella, T. C. Mitchell, The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316 , 1628-1632 (2007). [Abstract] [Full Text] U. Ohto, K. Fukase, K. Miyake, Y. Satow, Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316 , 1632-1634 (2007). [Abstract] [Full Text] K. A. Fitzgerald, D. T. Golenbock, The shape of things to come. Science 316 , 1574-1576 (2007). [Summary] [Full Text]