Tuning Immune Stimulation

Science's STKE  19 Jun 2007:
Vol. 2007, Issue 391, pp. tw218
DOI: 10.1126/stke.3912007tw218

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]