Brave new thymi

In Nature Biotechnology, Poznansky et al. describe a new procedure to mimic human thymic development through the engineering of an artificial thymic “organoid”. By using a 3-D matrix of tantalum-coated carbon seeded with murine thymic stroma, it was possible to recreate the conditions necessary for T lymphopoiesis from human CD34+ progenitors. By day 14 there were discrete populations of CD4+ and CD8+ single positive, as well as double positive, thymocytes. These T cells exhibited diverse TCR Vβ expression and, on functional analysis, the T cells were able to respond to a number of stimuli (IL-2, PHA, Con A) in an appropriate manner. Artificial thymic organoids may provide an ideal source of T cells to restore immune function in patients undergoing allogeneic stem cell transplantation, or in those infected with HIV.

Nature Biotech., 18, 729– 734 (2000)

Toxic flagellin

Enteroaggregative E. coli (EAEC) causes acute and persistent diarrhea, often associated with intestinal inflammation and impairment of growth in children. A soluble, heat-stable factor released by these bacteria rapidly induces IL-8 production from the intestinal epithelial cell line, Caco-2. In the Journal of Clinical Investigation, Steiner et al. show how they cloned and identified this Il-8–releasing factor as a flagellin, which is different from known E.coli flagellar proteins. Flagella purified from several EAEC isolates cause potent IL-8 release from Caco-2 cells, whereas an engineered aflagellar EAEC mutant does not cause this release. Finally, the cloned flagellin expressed in nonpathogenic E.coli causes release of IL-8 from Caco-2 cells. These findings may lead to a better understanding of how EAEC induces intestinal pathogenesis.

J. Clin. Invest., 105, 1769– 1777 (2000)

B cells: paying the Toll

B cells play an important role in host responses against Gram-negative bacteria. B cell responses to LPS are mediated by the Toll-like receptor (TLR)-4, a molecule also present on macrophages and neutrophils. In the Journal of Experimental Medicine, Ogata et al. show that another TLR, RP105, which is predominantly expressed on mature B cells, is involved in B cell responses to LPS. Gene targeting of RP105 in mice revealed impaired B cell responses to LPS. The group also showed functional cooperation between TLR-4 and RP105 in LPS-induced NF-κB activation. The important role of RP105 in B cell activation by LPS makes it a possible target for enhancement of the humoral response against Gram-negative bacteria.

J. Exp. Med., 192, 23– 29 (2000)

Avoiding death with TRADD

Functions of the TNFR superfamily are mediated by TNFR-associated factors (TRAFs). TNF-α induces apoptosis, but TRAF-2 can suppress this by the recruitment of cIAPs for the direct inhibition of caspase activation. In Cell, Park et al. reveal a newly identified mechanism for TRAF-2 signaling. TRAF-2 can be recruited to activated TNFR-1 directly or indirectly via the adaptor protein TRADD. They show that TRAF-2–TRADD binding is mediated by an extensive protein-protein interface and that this binding is of a much higher affinity than the TRAF-2–TNFR-1 interaction. They also show that TRAF-2 signaling is more readily initiated by TRADD than by direct receptor–TRAF-2 interactions, and that TRADD mutations result in highly potent apoptosis induction. This indicates that TRAF-2-TRADD interactions are extremely sensitive to affinity changes.

Cell, 101, 777– 787 (2000)

Dominating chemokines

Chemokine gradients are involved in directing T cell migration. In the Journal of Immunology, Bromley et al. reasoned that a chemokine gradient leading past, rather than towards, the APC may disrupt T cell activation by preventing the T cell from stopping long enough to form the immune synapse (IS). Using a transmigration assay, this group show that migration signals produced by receptors CCR7 (SLC and MIP-3) and CXCR3 (IP-10) are dominant over TCR signals and block or prevent IS formation, whereas signals produced by CXCR4 (SDF-1), CCR2 (MCP-1), CCR4 (MDC) and CCR5 (RANTES and MIP-1) are submissive to TCR signals. Thus, dominant chemokine gradients represent another mechanism for T cell ignorance of agonist MHC-peptide complexes.

J. Immunol., 165, 15– 19 (2000)

T cells low on perforin

In the Journal of Experimental Medicine, Appay et al. have used class I MHC–peptide tetrameric complexes in conjunction with intracellular staining to dissect the functional phenotype of circulating HIV-1– and CMV-specific CD8+ T cells. CD8+ T cells, specific for both HIV and CMV antigens, produce antiviral cytokines and chemokines (IFN-γ, TNF-α and MIP-1β), although a subset of tetramer-reactive CD8+ T cells secretes only IFN-γ and MIP-1β. Importantly, HIV-specific CD8+ T cells expressed significantly less perforin than CMV-specific CD8+ T cells. Reduced perforin expression is linked with persistent CD27 expression and poor specific lysis ex vivo . This suggests that HIV-1–specific CD8+ T cells show impaired maturation and cytolytic activity.

J. Exp. Med., 192, 63– 76 (2000)

Inhibition of angiogenesis

Most tumor cells do not express MHC class II molecules, but in the June issue of Immunity Qin and Blankenstein show that CD4+ T cells can play a role in rejecting class II tumors. Immunity against a class II tumor in mice is IFN-γ–dependent, but IFN-γR expression is not required on tumor cells, T cells or hematopoietic cells in the priming phase. However, successful immunity requires IFN-γR expression on nonhemapoietic cells for the effector phase and involves inhibition of tumor-induced angiogenesis, the mechanism of which is not yet elucidated. This shows that an effective antitumor response involves communication between CD4+ T cells and nonhematopoietic cells.

Immunity, 12, 677– 686 (2000)