A matter of life and death

How can tumor necrosis factor (TNF), a potent inducer of apoptosis, also be crucial for cellular proliferation and differentiation? In Cell, Micheau and Tschopp show that binding of TNF to its receptor, TNFR1, induces the formation of a membrane-associated complex that includes the adaptor and signaling molecules RIP1, TRAF2 and TRADD. A second complex is subsequently formed in the cytoplasm that is devoid of TNFR1 but contains caspase-8, caspase-10 and another adaptor molecule, FADD. In TNF-resistant cells, the first complex activates the NF-κB pathway, resulting in induction of the anti-apoptotic protein FLIPL, which inhibits caspase-8 activity of the second complex. In contrast, TNF-sensitive cells do not induce FLIPL and thus permit activation of the caspase-dependent death cascade. Thus, the NF-κB pathway checks TNF-mediated life-and-death signals. PL

Cell 114, 181–190 (2003)

Making a thymus

Thymus development begins around embryonic day 10–11 (E10–11) when an epithelial bud is formed. By E12 this epithelium is surrounded by mesenchyme, but its function in thymus development is unclear. In the Journal of Experimental Medicine, Anderson and colleagues showed that proliferation of embryonic thymic epithelial cells is dependent on the presence of mesenchyme, which secretes fibroblast growth factors 7 and 10. However, mesenchyme was dispensable for E12 thymic epithelial cell differentiation. Thus, thymic epithelial cell expansion requires mesenchyme. Whether thymic epithelial cell differentiation is completely autonomous or requires inductive signals before E12 is not known. JDKW

J. Exp. Med. 198, 325–332 (2003)

Sentry duty

Chemokines not only are important in attracting cells but also have antibacterial activities. In the Journal of Immunology, Shimaoka et al. show that chemokines recognize and mediate the uptake of bacteria. CXCL16 is a membrane-bound chemokine that has been independently identified as a scavenger receptor for oxidized lipoprotein and phosphatidylserine. Now it is clear that CXCL16 can also mediate the uptake of Escherichia coli and Staphylococcus aureus by dendritic cells and macrophages in a serum-independent way. The chemokine domain, but not the mucin stalk, of CXCL16 is important for the uptake of bacteria. Thus, while acting as a chemokine for T cells, CXCL16 also serves as a pathogen-recognition molecule. PL

J. Immunol. 171, 1647–1651 (2003)

Driving polarity

Neutrophils respond to chemoattractants by polarizing cytoskeletal assemblies involved in cell motility. In Cell, Bourne and colleagues investigate how neutrophils show an unique ability to polarize even in uniform concentrations of chemoattractant. Neutrophils maintain polarity by the use of two distinct cytoplasmic assemblies: 'frontness' is determined by Gi-coupled chemoattractant receptors that activate PI3P synthesis and Rac-dependent F-actin polymerization, whereas 'backness' is signaled by distinct G proteins, G12 and G13, that trigger the Rho-dependent kinase Rock and Rho and lead to myosin II–dependent inhibition of Rac- and PI3P-dependent responses. The same chemoattractant receptor can initiate neutrophil asymmetry by activating opposing signaling pathways simultaneously, thus establishing self-organizing assemblies that inhibit each other. LAD

Cell 114, 201–214 (2003)

The importance of being marrow

Secondary lymphoid organs contain T cell zones where dendritic cells (DCs) initiate the primary T cell response. In Nature Medicine, Feuerer et al. show that CD11c+ DCs in the bone marrow, a primary lymphoid organ by definition, can present antigen to naive T cells and initiate a primary immune response. Ovalbumin (OVA) challenge of wild-type or splenectomized alymphoblastic mice adoptively transferred with naive OVA-specific T cells generated a primary immune response in the bone marrow, as assessed by multicellular T cell–DC cluster formation, CD69 up-regulation and proliferation. Rechallenge of mice devoid of secondary lymphoid organs with B16-OVA tumor cells showed systemic proactive immunity and memory generation. Thus, the bone marrow not only mediates hematopoiesis but also helps generate systemic T cell immunity. JDKW

Nat. Med. 10 August 2003 (doi: 10.1038/nm914)

Functioning phagosomes

Phagosomes help macrophages to remodel tissue, clear apoptotic cells and contain the spread of intracellular pathogens. Galectin-3, a member of the β-galactoside-binding family of animal lectins, is abundant in phagosomes. In the Journal of Clinical Investigation, Sano et al. generated galectin-3 (Gal3)-deficient mice to investigate whether this lectin is involved in phagocytosis. Gal3-deficient macrophages had impaired phagocytosis of immunoglobulin G (IgG)-opsonized erythrocytes and apoptotic cells both in vitro and in vivo. Confocal microscopy showed Gal3 colocalized with the F-actin-rich phagocytic cups and phagosomes of wild-type macrophages containing IgG-opsonized erythrocytes. Consistently, the FcγR-mediated F-actin rearrangement of wild-type macrophages was impaired in Gal3-deficient cells. Thus, Gal3 is essential for phagocytosis, but how this lectin functions during this process remains to be elucidated. JDKW

J. Clin. Invest. 112, 389–397 (2003)

Tpl2 connectivity

Ligation of tumor necrosis family (TNF) receptors such as CD40 and TNFR initiates B cell activation and survival. T cells expressing CD40L trigger CD40 signaling through activation-associated TRAF molecules, which turn on multiple kinase pathways (JNK, ERK and p38). B cells then switch immunoglobulin class and generate memory plasma cells. In the EMBO Journal, Eliopoulos et al. link the serine-threonine kinase Tpl2 to TRAF6-mediated ERK activation after CD40 engagement. Tlp2 is recruited to the CD40 cytoplasmic domain, where it forms a physical association with TRAF6. Tpl2-deficient cells do not transmit TRAF6 signals in response to CD40 or TNFR1 ligation. As a result, Tpl2-deficient B cells show defects in immunoglobulin E (IgE) but not IgG1 switching, indicating that Tpl2-TRAF6 signals bias isotype switching. LAD

EMBO J. 22, 3855–3864 (2003)

Research notes written by Laurie A. Dempsey, Peter Lee and Jamie D.K. Wilson.