Mucosal immunology

Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Macpherson, A. J. & Uhr, T. Science 303, 1662–1665 (2004)

This study describes a mechanism to explain why inflammatory responses to commensal bacteria in the intestines are rare, despite the fact that these bacteria share many molecular patterns with pathogenic bacteria that are recognized by the immune system. In a mouse model of intestinal challenge with Enterobacter cloacae, this commensal bacterium was carried in dendritic cells (DCs) to the mesenteric lymph nodes (MLNs), which confined the live commensals in DCs to the mucosal immune system and so avoided systemic priming (unlike for pathogenic bacteria). Commensal-loaded DCs induced B-cell production of IgA in the MLNs, which was shown to restrict commensal penetration of the intestinal epithelium to low levels.

Immune regulation

Human bone-marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase mediated tryptophan degradation. Meisel, R. et al. Blood 4 March 2004 (doi: 10.1182/blood-2003-11-3909)

Human bone-marrow stromal cells (BMSCs) are known to inhibit allogeneic T-cell responses and are therefore being investigated to promote haematopoietic engraftment when co-transplanted with haematopoietic stem cells. Previous controversial reports have indicated that transforming growth factor-β1 and hepatocyte growth factor might be responsible for this effect. This study shows that the expression and activity of indoleamine 2,3-dioxygenase (IDO) is upregulated in BMSCs after exposure to low levels of interferon-γ, which can be generated by allogeneic T cells. IDO is responsible for the catabolism of tryptophan, which has previously been identified as a T-cell inhibitory effector mechanism. The fact that IDO is not constitutively expressed by BMSCs should enable this inhibitory mechanism to be modulated depending on the therapeutic application.

Signalling

The STAT3 isoforms α and β have unique and specific functions. Maritano, D. et al. Nature Immunol. 14 March 2004 (doi: 10.1038/ni1052)

The truncated form of signal transducer and activator of transcription 3 (STAT3β) lacks the carboxy-terminal transcriptional activation domain and is thought to be dominant negative to the full-length form STAT3α in transducing signals through cytokine receptors. But new research has shown that STAT3β can carry out the essential developmental functions of STAT3α and rescue the embryonic lethality of complete STAT3 deletion, and can also activate transcription of certain target genes, such as those encoding acute-phase proteins in the liver. However, STAT3β cannot compensate for all functions of full-length STAT3α, such as regulating signalling through the interleukin-6 receptor, indicating that the two forms are non-redundant.

Innate immunity

A Toll-like receptor that prevents infection by uropathogenic bacteria. Zhang, D. et al. Science 303, 1522–1526 (2004)

In this study, Zhang et al. identified a novel Toll-like receptor, termed TLR11, which seems to sense uropathogenic bacteria and initiate immune responses that lead to their clearance. TLR11 was discovered in a mouse liver expressed-sequence tag database during a search for sequences that have homology with the Toll/interleukin-1 receptor domain. Further experiments showed abundant expression of TLR11 by both kidney and bladder epithelial cells. TLR11-deficient mice were subsequently found to be highly susceptible to kidney infections after intra-urethral challenge with uropathogenic Escherichia coli. The authors speculate that humans are susceptible to urinary-tract infections because they have a truncated form of TLR11, which might be functionally inactive.

Cell migration

Locomotion of monocytes on endothelium is a critical step during extravasation. Schenkel, A. R. et al. Nature Immunol. 5, 393–400 (2004)

The current paradigm of leukocyte extravasation states that cells undergo a sequential series of steps when migrating from the blood into tissues — tethering, rolling, adhesion and diapedesis. So, how do leukocytes that adhere to the endothelium locate and move towards the endothelial-cell junctions where diapedesis occurs? In this paper, the interaction of monocyte β2 integrins with their respective endothelial ligands, which is known to mediate adhesion, was also shown to have a distinct role in the subsequent 'locomotion' to cellular junctions. Blockade of either β2 integrins or their endothelial ligands caused monocytes to spin and fail to position themselves at cellular junctions, thereby defining a new step in the regulation of leukocyte diapedesis.

Tumour immunology

Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and γδ T cells. Street, S. E. A. et al. J. Exp. Med. 199, 879–884 (2004)

The extent to which innate immune cells contribute to immune surveillance against tumours is still controversial. In this paper, Street et al. studied the mechanism by which wild-type mice reject transplants of MHC class-I-deficient B-cell lymphomas. These tumour cells were found to be rejected by mice lacking various immune-cell populations — except those depleted of natural killer (NK) cells or NK cells and γδ T cells. This tumour-specific response was shown to be perforin dependent, because perforin-deficient mice succumbed to spontaneous development of B-cell lymphomas. Therefore, this study indicates a crucial role for innate immune cells in the surveillance of B-cell lymphomas. The mechanism by which NK cells and γδ T cells are stimulated by MHC class-I-deficient tumour cells remains unclear.