T-cell responses

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. Das, A. et al. J. Exp. Med. 11 August 2008 (doi:10.1084/jem.20072076)

This study provides a potential explanation for the failure of viral control and liver damage in patients with chronic hepatitis B infection. The inflamed livers of these individuals contained a large number of non-virus-specific CD8+ T cells that were impaired in their ability to produce interleukin-2 and proliferate in response to T-cell receptor ligation, although their production of pro-inflammatory cytokines was preserved. This defective phenotype was shown to be associated with the downregulation of CD3 ζ-chain and CD28 expression, restoration of which could rescue the defect. Further in vitro observations suggested that deprivation of arginine in the inflamed hepatic microenvironment might be a contributing factor to the disease-associated T-cell defect, which is consistent with the finding that low levels of arginine and arginase in the serum and liver correlated with disease activity.

Allergy

Phosphorylation of SNAP-23 by IκB kinase 2 regulates mast cell degranulation. Suzuki, K. & Verma, I. M. Cell 134, 485–495 (2008)

By releasing their granule contents, mast cells are the main effector cells of allergic reactions. However, the mechanisms that regulate mast-cell degranulation were poorly defined. This study now shows that inhibitor of nuclear factor-κB kinase 2 (IKK2) has a crucial role in this process by phosphorylating the SNARE protein SNAP23. Mast-cell-deficient mice that were reconstituted with IKK2-deficient mast cells showed reduced anaphylactic responses compared with control animals owing to defective mast-cell degranulation. Further studies revealed that IKK2 co-localizes with SNAP23 in membrane rafts following IgE-mediated stimulation of mast cells. IKK2 then phosphorylates SNAP23 on two serine residues, which leads to the formation of a SNARE protein complex that catalyses granule fusion with the plasma membrane to release granule components. In addition, IKK2 was shown to be involved in late-stage allergic reactions involving mast-cell secretion of pro-inflammatory cytokines.

Mucosal immunology

Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation. O'Mahony, C. et al. PLoS Pathog. 4, e10000112 (2008)

Commensal bacteria in the intestine are known to influence immune homeostasis and host defence against pathogens. Now, O'Mahony et al. show that the probiotic microorganism Bifidobacterium infantis provides protection from immunopathology induced following infection with Salmonella typhimurium in mice. Consumption of B. infantis prior to S. typhimurium infection inhibited the activation of nuclear factor-κB and the production of pro-inflammatory cytokines in the intestine despite equivalent colonization by the pathogen in the intestines of mice that were not fed B. infantis. Interestingly, there was an increase in the proportion of regulatory T cells in the intestines of B. infantis-fed mice compared with control mice. Furthermore, adoptive transfer experiments showed that inhibition of pathogen-induced immunopathology was mediated by regulatory T cells, indicating that B. infantis curbs intestinal immunopathology in part through its effects on this T-cell subset.