Cytokines

IL-23 produced by CNS-resident cells controls T-cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. Becher, B., Durell, B. G. & Noelle, R. J. J. Clin. Invest. 112, 1186–1191 (2003)

Interleukin-23 (IL-23) consists of a unique p19 subunit and the p40 subunit of IL-12, and is crucial for the development of experimental autoimmune encephalomyelitis in mice. Becher et al. use p40-deficient mice to generate irradiation bone-marrow chimaeras and show that in the absence of p40 expression by irradiation-resistant cells, previously activated antigen-reactive cells infiltrate the central nervous system (CNS), but do not induce encephalitogenicity. In addition, disease induced by immunization is markedly diminished when p40 is absent from irradiation-resistant cells and this is associated with a bias towards the production of T helper 2-type cytokines by infiltrating cells. The authors, therefore, suggest that p40 expression by CNS-resident cells contributes to T-cell polarization and thereby modulates disease pathogenesis.

Transplantation

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Changelian, P. S. et al. Science 302, 875–878 (2003)

The development of effective immunosuppressive agents that are targeted specifically to immune cells and do not produce serious side effects remains a pressing need for the prevention and treatment of transplant rejection. This study reports pre-clinical trials of a new immunosuppressive agent (CP-690,550) that prolonged survival in both a mouse model of heart transplantation and a cynomolgus monkey model of kidney transplantation, but that did not result in the dose-limiting side effects that are associated with present therapies. CP-690,550 inhibits Janus kinase 3 (JAK3), which is crucial for signalling through cytokine receptors that use the common γ-chain and, therefore, for development and homeostasis of immune cells. It is the first JAK3 inhibitor to have shown efficacy in non-human primates.

Immunotherapy

A critical role for OX40 in T cell-mediated immunopathology during lung viral infection. Humphreys, I. R. et al. J. Exp. Med. 198, 1237–1242 (2003)

Respiratory infections are an important example of how an over-active T-cell response can be more of a hindrance than a help, with T-cell responses resulting in airway occlusion and pathology. Previous T-cell-targeted therapies have affected both bystander and antigen-specific T cells, which might result in dangerous immunosuppression. These authors used an OX40–Ig fusion protein to target recently activated T cells specifically. OX40 signalling prevents the death of activated T cells, but it is not expressed by naive T cells. Interference with this T-cell survival signal in a mouse influenza model reduced immunopathology without preventing virus clearance.

Natural Killer Cells

The mature activating natural killer cell immunologic synapse is formed in distinct stages. Orange, J. S. et al. Proc. Natl Acad. Sci. USA 100, 14151–14156 (2003)

The interface between a natural killer (NK) cell and its target cell — the activating NK-cell immunological synapse — is highly organized. In this study, Orange et al. show that CD2 and CD11b, similar to CD11a, co-localize with filamentous actin in the peripheral supramolecular activation cluster (pSMAC), whereas perforin accumulates in the central SMAC (cSMAC). Polarization of CD2, CD11a and CD11b to the pSMAC was dependent on actin polymerization and Wiskott-Aldrich syndrome protein (WASP), but independent of microtubule function. By contrast, perforin accumulation at the cSMAC was dependent on actin polymerization, WASP and microtubule function. In addition, the rate of cSMAC perforin accumulation was slower than the recruitment of receptors to the pSMAC, indicating that formation of the NK-cell immunological synapse is a highly regulated sequential process.

Mucosal Immunology

Spheniscins: avian β-defensins in preserved stomach contents of the king penguin, Aptenodytes patagonicus. Thouzeau, C. et al. J. Biol. Chem. 2 October 2003 (doi:10.1074/jbc.M306839200)

In this paper, Thouzeau and colleagues have identified two new avian antimicrobial peptides in the stomach of the male king penguin. These peptides, known as spheniscin 1 and 2, belong to the β-defensin family and have broad antimicrobial activity against pathogenic bacteria and fungi. The levels of spheniscin 1 and 2 are higher during periods of food storage than when the birds are digesting and interestingly, a drop in spheniscin levels correlated with a change from food storage to digestion. These antimicrobial peptides act to protect the surface of the bird's gastrointestinal tract from damage or invasion, and might be important for the long-term preservation of stored food, which can be important for chick survival.