T-cell memory

Serine protease inhibitor 2A is a protective factor for memory T cell development. Liu, N. et al. Nature Immunol. 15 August 2004 (doi:10.1038/ni1107).

The mechanisms by which antigen-specific CD8+ T cells escape programmed cell death (PCD) and become memory cells are not well established. Now, Ni Liu et al. report a crucial protective role for serine protease inhibitor 2A (SPI2A), which inhibits PCD triggered by cathepsins. By screening for candidate genes, the authors showed that SPI2A expression was upregulated by memory T cells but not by naive T cells. Effector T cells from bone-marrow chimeric mice expressing an SPI2A transgene showed suppressed cathepsin B activity and PCD induction. Accordingly, more virus-specific memory cells survived in these mice following viral infection, indicating that commitment to the memory lineage is facilitated by the upregulation of protective genes.

Lymphoid architecture

Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Allen, C. D. C. et al. Nature Immunol. 1 August 2004 (doi:10.1038/ni1100).

This study explores the mechanisms involved in segregating B cells to the dark and light zones of germinal centres (GCs), in which they carry out somatic hypermutation and antigen-driven selection, respectively. By generating fetal liver chimeras, the authors show that deficiency in the chemokine receptor CXCR4 results in disrupted GC compartmentalization. Immunohistochemical analysis indicated that centroblasts undergoing somatic hypermutation expressed high levels of CXCR4 and localized to the dark zone, which is consistent with higher expression of the CXCR4 ligand CXCL12 in the dark zone compared with the light zone. By contrast, expression of CXCR5 and its ligand CXCL13 were concentrated in the light zone and contributed to recruitment of cells to this zone.

Inflammation

Tumour necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. Xanthoulea, S. et al. J. Exp. Med. 200, 367–376 (2004)

Although the pro-inflammatory effects of TNF are beneficial to host defence, they can be harmful if not controlled. Proteolytic cleavage (shedding) of cell-surface TNF receptor p55 (TNFRp55) modulates TNF function, and in humans, impaired receptor shedding is linked to a group of autoinflammatory syndromes. In this study, knock-in mice heterozygous or homozygous for a non-sheddable TNFRp55 spontaneously developed TNF-dependent chronic inflammation of the liver and were increased in their susceptibity to TNF and lipopolysaccharide toxicity, as well as chronic inflammatory disease. By contrast, these animals showed increased resistance to infection with Listeria monocytogenes. These effects indicate a crucial role for TNFRp55 shedding in the regulation of the effects of TNF in vivo.