Like a jigsaw puzzle, in which individual pieces form a larger, more complex image, the innate immune system is composed of many individual elements that together form an intricate defense network. The now well documented Toll-like receptors make up only one part of this system. Here we focus on four non-Toll-like innate immune protein families in a series of specially commissioned review articles available free online (www.nature.com/ni/focus/innateproteins) during December 2006. Artwork by Lewis Long.

Correlations between diacylglycerol metabolism and T cell anergy have been reported, but a causative relationship has not been established. The Gajewski and Koretzky groups (pp 1166 & 1174, News & Views by Mueller, p 1132) now link altered diacylglycerol metabolism with the anergic state. The original immunofluorescence image (bottom, by K. Praveen, Y. Zha and T.F. Gajewski) shows defective recruitment of RasGRP1 (green) to the contact site between a T cell overexpressing diacylglycerol kinase-α and an antigen-presenting cell (blue). Artwork by Lewis Long.

In higher vertebrates,phagocytosis is accomplished by 'professional' phagocytes, but B lymphocytes are not phagocytic. Sunyer and colleagues (p 1116) show that B lymphocytes in teleost fish and xenopus have phagocytic capabilities and suggest that mammalian B lymphocytes may be of phagocytic ancestry. The original scanning electron microscopy image (bottom) shows neutrophil-like (right) and lymphocyte-like (left) teleost fish cells. 'Bumps' represent ingested latex beads. Artwork by Lewis Long.

Brain inflammation associated with experimental autoimmune encephalomyelitis or certain infections is linked to interleukin 17 (IL-17)-producing helper T cells. The Ghilardi and Hunter groups (pp 929 & 937; News and Views by Colgan and Rothman, p 899) find that IL-27 blocks development of IL-17-producing T cells. The original immunohistochemical image (by Jason Stumhofer and Emma Wilson) shows reactive astrocytes (brown) in the brain of an IL-27 receptor-deficient mouse infected with Toxoplasma gondii. Artwork by Lewis Long.

Toll-like receptor 5 (TLR5) recognizes bacterial flagellin. Akira and colleagues demonstrate that CD11c+ lamina propria cells have high expression of TLR5 and may help the immune system distinguish between pathogenic and commensal bacteria. The original immunofluorescence image (by Satoshi Uematsu and Myoung Ho Jang) shows CD11c+ cells (red) expressing TLR5 (green) in the lamina propria of the small intestine. Artwork by Lewis Long.

Drosophila cells express multiple receptors capable of sensing bacterial products. Silverman and colleagues demonstrate that PGRP-LE, a drosophila receptor recognizing bacterial peptidoglycan, exerts distinct extracellular and intracellular functions. The original confocal micrograph (by Camilla Peach and Deniz Erturk-Hasdemir) shows drosophila cells (nuclei, blue) expressing intracellular PGRP-LE (yellow). Art work by Lewis Long.

Whether RNA interference is an important component of the drosophila defense against virus infection in vivo has been unclear. Imler and colleagues (p 590) now demonstrate that for certain virus infections,RNA interference is a critical defense mechanism in flies. Fat body cells (nuclei in red) are shown infected with Sindbis virus (E1 glycoprotien in green). Art work by Lewis Long, inspired by an immunofluoresence micrograph by Imler and colleagues.

The continued spread of the H5N1 influenza virus emphasizes the importance of anti-influenza immune defense mechanisms. Three papers in this month's issue of Nature Immunology examine the immune cell response to influenza virus infection and discuss the challenge this virus poses to population-based immunity (pp 443, 449 and 517). Image shows an agglomeration of influenza viruses. Artwork by Lewis Long.

Immune cells respond to a variety of external cues, suggesting specialized microenvironments, depicted by the various doorways, can profoundly influence their function. This month we present a series of commissioned review articles that focus on unique anatomical niches that are key to immune cell development and function. These reviews and additional internet-only content are available free online (www.nature.com.ni/focus/niches/index.html) during April 2006. Artwork by Lewis Long.

Skin Langerhans cells provide a first line of protection against pathogens. Merad and colleagues (p 265; News and Views by Palucka and Banchereau, p 223) identify Langerhans cell precursors as Gr-1hi monocytes (red) that migrate into epidermis (blue) and express langerin (green) as they differentiate into Langerhans cells. The image shows a large area of skin surveilled by developing Langerhans cells (red, green). Immunofluorescence by Milena Bogunovic. Art work by Lewis Long.

Genetic approaches for identifying immune functions can yield unexpected findings. Beutler and colleagues (p. 156; News and Views by Tough, p 127) characterize '3d', a mutation that alters the endoplasmic reticulum protein UNC-93B (yellowish green). This protein is not found in lysosomes or acidified endosomes (red) and is required for both Toll-like receptor signaling and exogenous antigen presentation. Original image by Benjamin E. Steinberg. Artwork by Lewis Long.

How regulatory T cells control autoimmunity in vivo is controversial. Bluestone and colleagues (p 83; News and Views by Bousso, p 11) show using two-photon laser-scanning microscopy that regulatory T cells interact directly with dendritic cells but not islet-specific T helper cells in pancreatic lymph nodes. The image depicts regulatory T cells (red) swarming around dendritic cells (yellowish green). Original image by Qizhi Tang. Artwork by Lewis Long.