In this issue

Abstract

Cover image

The cover is based on a spinal cord histology section taken from a TNFR2^−/− mouse adoptively transferred with TNFR2^−/− Treg cells prior to immunization with MOG_35–55 to induce EAE. The section is stained with Luxol Fast blue to detect demyelination; Luxol Fast Red, which detects inflammatory infiltration, is the counterstain. The image is taken from the article by Tsakiri et al. (pp. 403–412) in which it is shown that TNFR2 on non-haematopoietic cells is necessary for Treg-cell suppressive activity and repression of EAE development. The colour of the image has been digitally altered for the cover.

CMV: Fine tuning the NK-cell response during chronic hepatitis infection

Two recent studies reported on the expansion of NKG2C⁺ NK cells during chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. In this issue, Béziat et al. show that the expansion of NKG2C⁺CD56^dim NK cells observed in the blood and liver of HBV- or HCV-infected patients is dependent on infection with human cytomegalovirus (HCMV). The expanded NKG2C⁺ NK cells display a terminally differentiated phenotype with strong functional responses against HLA-E-expressing targets and antibody-coated targets but not to IL-12/IL-18 stimulation. Interestingly, these NKG2C⁺ NK cells clonally or oligoclonally express self-specific KIRs that block NKG2C-mediated activation, possibly explaining the limited immune pathology associated with the presence/expansion of this highly cytotoxic subset. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection, resulting in the clonal expansion and differentiation of polyfunctional NK cells expressing self-specific inhibitory KIRs.

pp. 447–457

Keep that thymus! Affinity maturation of antibodies requires an intact thymus in the adult

The thymus generates T cells, which in turn provide help to B cells to produce antibodies, which constitute the only means of protection against some microbial organisms and their toxins. Whether the thymus contributes other functions to promote antibody responses is not known. In this issue, AbuAttieh et al. show that thymus integrity enables the selection of B cells producing high-affinity antibodies, but is dispensable for the generation of long-lived antibody secreting cells. The defective affinity maturation of antibodies occurs in spite of normal T-cell repertoires in mice with disrupted thymuses, which suggests a novel thymic-dependent mechanism for producing high-affinity antibodies. This finding also explains the deficient responses to vaccination in pediatric cardiac transplantation patients who had their thymus removed at the time of surgery. Finding the molecular mechanisms by which the thymus controls antibody affinity maturation will inspire new approaches to manipulating immunity for the purpose of enhancing or suppressing antigen-specific responses.

pp. 500–510

All roads lead to Rome: IL-17 drives Th1 immunity following BCG vaccination

Mycobacterium bovis Bacille Calmette Guerin (BCG) is the only available vaccine against tuberculosis. The generation of effective type 1 T-helper (Th1) cell responses is required for immunity against tuberculosis, but the factors that drive effective generation of vaccine-induced Th1 responses are not completely understood. In this issue, Gopal et al. show that following BCG vaccination, the production of interleukin (IL)-17 by Th17 cells overcomes the inhibitory effects of IL-10 on the generation of vaccine-induced Th1 responses. Following exposure to BCG, mediators such as prostaglandin-E2 (PGE2) promote IL-10 production, limit IL-12 production and Th1 host responses; however, PGE2 also induces IL-23 production and Th17-cell generation. The ability of IL-17 to down-regulate IL-10 and induce IL-12 production in DCs allows the subsequent generation of Th1 responses. These findings highlight how vaccine-induced Th17 cells can be targeted to induce optimal Th1 immunity and may be exploited to improve vaccine strategies against tuberculosis.

pp. 364–373

Constraints for monocyte-derived dendritic cell differentiation

The chronic activation of Toll-like receptors (TLRs) leads to persistently impaired macrophage or DC functionality. TLR signals trigger several negative feedback mechanisms but it is not known which of these lead to long-lasting tolerance to further stimulatory signals. It is also not yet understood how monocyte-derived DCs (MoDCs) develop in inflamed tissues in spite of the constant stimulation received during their differentiation. In this issue, Fekete et al. examine the role of several DC inhibitory mechanisms in a robust model of MoDC inactivation induced by early TLR signals during differentiation. The authors find that the activation-induced SOCS1, IL-10, STAT-3, miR146a and CD150 molecules have short-term inhibitory effects on cytokine production, and that IRAK-1 downregulation is linked with persistent MoDC inactivation. Early activation of developing MoDCs allows transient cytokine production that is followed by persistent MoDC inactivation and the preservation of a tissue-resident, non-migratory phenotype.

pp. 458–469

From our sister journals – a screening tool for therapeutic antibodies

The development of bio-therapeutics is a long and winding road that is dependent on many variables along the way. One of these factors is the stability of a protein and its propensity for forming aggregates. Aggregates, however small the amount present, are highly undesirable due to decreased biological activity of the protein, and the potential to trigger unintended immune responses. A current standard method of analyzing protein stability and aggregate formation is size-exclusion chromatography (SEC). SEC however, has several drawbacks such as its inability to detect conformational differences. In this issue, Trout and colleagues report a novel screening tool based on dye (i.e. thioflavin T (ThT))-binding properties. ThT binds nonspecifically to the β-sheet-rich amyloid-type protein aggregates. The major advantage of ThT binding is the short duration of testing compared to SEC – results can be obtained within days as opposed to months.

pp. 127–132