In this issue
In this Issue: Eur. J. Immunol. 12'12
The cover image shows a pancreatic tumor cell layer with E-cadherin expression stained in green. The T3M4 pancreatic tumor cell line was exposed to polymorphonuclear neutrophils (PMNs), which lead to dyshesion of the cell layer and a decrease in the E-cadherin expression. The image is taken from Gaida et al. (pp. 3369–3380) where the authors show that exposure of tumor cells to PMNs induces celllayer dyshesion and decreased E-cadherin expression. The authors further show that E-cadherin degradation by other means increases the migratory capacity of pancreatic tumor cells and that E-cadherin expression correlates negatively with PMN infiltration in pancreatic ductal adenocarcinoma patients. All these data suggest that cleavage of E-cadherin by PMNs could contribute to invasive tumor growth.
Why IL-18 at the microvesicle level?
Despite its indubitable importance in physiological and pathological conditions, little is known about IL-18 synthesis, elaboration and secretion in the extracellular milieu. In this issue, Gulinelli et al. report that IL-18 associates with microvesicles shed by human macrophages in a P2-dependent fashion. Nucleotides are released from the cells upon microbial infection, cell damage or inflammation and act as an “alert signal” towards immune cells by activating P2 receptors. ATP and its pharmacological analog BzATP induce microvesicle shedding from human ex vivo macrophages by stimulating the P2×7 receptor subtype. An increase in the intracellular calcium concentration is important to induce microvesicle shedding, while the presence of bacterial endotoxin (LPS) or activation of TLR4 signalling are not required for microvesicle shedding or pro-IL-18 synthesis. Caspase-1 inhibitors reduce microvesicle shedding but do not block pro-IL-18 cleavage. These data reveal a nucleotide-based mechanism responsible for the shedding of microvesicles, with which pro-IL-18 and IL-18 associate.
10.1002/eji.201142268, pp 3334–3345
Epithelial cells share their stress with DCs
Intestinal epithelial cells (IECs) are continually exposed to luminal bacteria, but are normally tolerant to them, thereby conditioning dendritic cells (DCs) to a hypo-inflammatory state. However, when exposed to stress signals such as high concentrations of extracellular ATP, epithelial cells increase their responses to TLR ligands. In this issue, Yao et al. examine the crosstalk between IECs and DCs and show that murine IECs stimulated with the TLR1/2 ligand Pam3CSK4 plus ATP increase cytokine and CD80 expression by DCs. These IEC-conditioned DCs in turn induce greater proliferative and cytokine responses in CD4+ T cells given either recall or primary antigen stimulation. Evidence that intra-rectal administration of the non-hydrolyzable ATP analog ATPγS enhances IEC production of IL-6 and Cxcl1 suggests that endogenous TLRs and stress signals also activate IECs in vivo. These results help explain how the vicious cycle of epithelial injury and T-cell activation to components of commensal bacteria is propagated in inflammatory bowel disease.
10.1002/eji.201142213, pp 3310–3321
IRF4 makes the difference: IL-17 production by innate lymphocytes and conventional T cells
IL-17 is the hallmark cytokine of inflammatory type 17 responses driven by effector cell types such as CD4+ Th17, CD8+ Tc17, and innate γδ T cells. Type 17 responses play important roles in the defence against infections with fungi and extracellular bacteria and in autoimmune disorders such as MS or rheumatoid arthritis. Previously, the transcription factor IRF4 was shown to be required for the differentiation of Th17 and Tc17 cells, leading to resistance of IRF4 deficient mice to EAE, a mouse model of MS. In this issue, Raifer et al. demonstrate that the pathways used by innate and conventional T lymphocytes for type 17 different-iation in mice differ fundamentally, because innate lymphocytes produce IL-17 independently of IRF4. While conventional T cells acquire the capacity to produce IL-17 in the periphery in an IRF4-dependent response to pro-inflammatory cytokines, γδ T-cell instruction occurs in the thymus and requires the NF-κB members RelA and RelB instead of IRF4.
10.1002/eji.201142155, pp 3189–3201
ZNF385B: A new player in germinal center B-cell development
B cells have integrated control systems to expand high-affinity clones against exogenous antigens and eliminate inappropriate clones in a developmental stage-dependent manner. The involvement of a number of molecules in this regulatory system has been identified, although the details have yet to be fully clarified. In this issue, Iijima et al. demonstrate that ZNF385B is characterist-ically expressed in germinal center centro-blasts and involved in B-cell apoptosis in human B-cell lines. The longest transcript variant of ZNF385B directly interacts with p53 and induces apoptosis in B cells that is accompanied by up-regulation of PERP and FAS, downstream targets of p53, and caspase activation. In contrast, a ZNF385B deletion mutant corresponding to shorter isoforms inhibits apoptosis induced by CD20 cross-linking and BCR stimulation. These results suggest that ZNF385B is a new player in germinal center B-cell development and has both pro-apoptotic and anti-apoptotic activ-ities depending on the isoform. The relationship between ZNF385B and lymphomagenesis is also discussed.
10.1002/eji.201242530, pp 3405–3415
Flu-specific memory CD8+ T-cell function fizzles out
Memory CD8+ T cells reactive to internal antigens in influenza contribute to immune protection from multiple strains of the virus. This “heterosubtypic immunity” is known to decrease over time. In this issue, Humphreys et al. examine the ability of influenza-specific CD8+ T cells to protect from heterologous challenge in a mouse model of infection. The ability of memory CD8+ T cells to expand in response to secondary infection is maintained irrespective of how long after initial influenza infection hosts are challenged. However, the ability of memory CD8+ T cells to elicit anti-viral functions during challenge decays over time, and is associated with reduced avidity of the memory T cells. These findings suggest that the loss of heterosubtypic immunity over time is due, at least in part, to a loss of functional capacity of influenza-specific memory CD8+ T cells, possibly as a consequence of declining antigen levels and a concomitant loss of high affinity T cells.
10.1002/eji.201242575, pp 3235–3242