News & Views in 2008

Cross-presentation of antigens is essential for the responses of cytotoxic T cells to tumors and viruses. Two new papers offer insights into the subcellular compartment and types of dendritic cells that mediate cross-presentation.

Toll-like receptor signaling induces the production of proinflammatory cytokines and type I interferons. Inhibition of the kinase IRAK1 by the phosphatase SHP-1 provides reciprocal regulation of these pathways by dampening the former while enhancing the latter.

TLR4 somehow manages to activate both MyD88- and TRIF-dependent signaling. According to Medzhitov and colleagues, TLR4 engages MyD88 and TRIF sequentially at the cell surface and in endosomes, respectively, thereby providing access to distinct pools of signaling proteins.

The bone marrow contains specialized microenvironments that maintain blood cells and supply the requisite factors for their development. Newly identified bone marrow–resident dendritic cells create unique niches for mature B cells.

The homing of lymphocytes to secondary lymphoid organs occurs at specialized blood vessels, the high endothelial venules. Autotaxin, a phospholipid-producing enzyme secreted by high endothelial venule endothelium, is a new participant found to facilitate the entry of lymphocytes into secondary lymphoid organs.

Activation of the transcription factor NF-κB by Toll-like receptors must be controlled to avoid excessive inflammation. The tripartite-motif protein family member TRIM30α has now been shown to mediate a negative regulatory feedback mechanism curtailing such responses.

Basophils have long been suspected to be potent inducers of T helper type 2 differentiation. Sokol and colleagues now demonstrate that basophils are required for adoption of the T helper type 2 fate in vivo in response to allergens with protease activity.

Human immunodeficiency virus may direct its assault on gut-associated CD4⁺ T cells by means of the gut-homing integrin α₄β₇.

Both activation and termination of transcription factor NF-κB signaling require ubiquitin modification of pathway components. The E3 ligase Itch teams up with the NF-κB inhibitor A20 to edit the composition of ubiquitin chains on the signaling adaptor RIP, thereby limiting inflammatory responses.

Two groups demonstrate proteolytic activity for MALT1, a component of the signaling pathway mediating antigen receptor–dependent stimulation of the transcription factor NF-κB, and identify its first substrates.

Naive T cells can spend hours 'sampling' dendritic cells before making a stable conjugate with a single dendritic cell. It is the antigen 'dose' that determines how long this process takes.

Kruppel-like factor 2 is now shown to regulate chemokine receptor expression in lymphocytes, which leads to their homing to nonlymphoid organs after they leave the thymus.

Lymphocytes depend on endothelial adhesion molecules such as ICAM-1 and VCAM-1, upregulated with inflammation, to facilitate transmigration across junctional barriers. New data show that ALCAM replaces VCAM-1 in the CNS during the development of neuroinflammatory diseases such as multiple sclerosis.

Inducible regulatory T cells respond to TGF-β by upregulating Foxp3 expression. Tone and colleagues identify an enhancer site in Foxp3 that binds transcription factors Smad3 and NFAT, suggesting a means by which TGF-β regulates Foxp3 expression.

The prevailing paradigms ascribe the initiation of immune surveillance to the detection of foreign or inflammatory 'danger' signals. However, new work indicates that immune cells can detect early signs of cellular dysregulation that precede tumorigenesis, even in the absence of non-self signals and/or inflammation.

The T cell costimulatory protein LIGHT and coinhbitory protein BTLA share a common ligand, HVEM. Now CD160 is also shown to bind HVEM and deliver a potent inhibitory signal to CD4 T cells.