Cover image
The cover shows a modified electron microscopic image of HPV16‐virus‐like particle (HPV16‐VLP)‐internalization by NK cells. The colour added to the cover image is purely for aesthetic purposes and has no biological significance. The original, unmodified image is from Renoux et al. (pp. 3240–3252) in which the authors demonstrate that HPV16‐VLPs are taken up by NK cells by macropinocytosis. CD16 is shown to play a central role in the NK cell response to HPV16, being shown to be required for viral uptake, and for granzyme and cytokine release.
BMPs inhibit antibody production in human B cells
Bone morphogenetic proteins (BMPs) are part of the TGF‐β family of proteins. Whereas TGF‐β is an important negative regulator of the immune system, the role of BMPs in this respect is largely unknown. In this issue, Huse et al. investigate the functional effect of BMPs on human naive and memory B cells. The authors report that exogenously added BMPs inhibit CD40L/IL‐21‐induced antibody production. The mechanism for inhibition of antibody production varies between the different BMPs, as BMP‐7 mainly induces naive B‐cell apoptosis and BMP‐6 mainly inhibits differentiation to plasmablasts. In memory B cells, BMP‐6 induces increased expression of DNA‐binding protein inhibitor genes, but inhibits CD40L/IL‐21‐induced upregulation of the transcription factor XBP1, which is necessary for the late stages of plasmacytic differentiation. These findings suggest a role for BMPs in regulating the immune system as suppressors of B cells.
pp. 3135–3145
TAP prevents presentation of alternatively‐processed peptides
The peptide transporter TAP mediates the entry of peptide precursors from the cytosol into the ER where they are loaded onto MHC class I molecules. Some MHC class I‐presented peptides do not require the action of TAP or the proteasome and derive from alternative processing pathways. Interestingly, some of these alternatively processed peptides are only presented when there are impairments in the classical processing pathway and do not normally reach the cell surface in cells with intact classical processing. In this issue, Oliveira et al. show that the peptide transporter TAP actually prevents the presentation of this alternatively processed peptide repertoire in response to the overwhelming influx of competitor peptides in the ER. Strong over‐expression of the antigen‐encoding gene was needed to drive the alternatively processed peptide towards MHC class I surface display. Thus, TAP behaves like control lever in shifting the presented peptide repertoire gradually towards TAP‐independent or TAP‐dependent peptides.
pp. 3114–3124
Controlling pathological B cells in human lupus
Autoreactive B cells, like healthy ones, can be down‐regulated by a number of inhibitory receptors. In this issue, Kerekov et al. develop a chimeric protein molecule capable of cross‐linking of cell‐surface immunoglobulin (Ig) with the inhibitory complement receptor type 1 (CR1) and delivering a strongly suppressive signal to B cells. The authors investigate the effects of this protein chimera in a humanized SCID mouse model of lupus and report that the administration of this DNA‐like chimera to SCID mice repopulated with cells from SLE patients prevents the appearance of anti‐dsDNA antibodies, proteinuria and other lupus symptoms in the treated animals. Furthermore, administration of the chimeric molecule re‐establishes tolerance to native DNA in transferred SCID mice. Taken together, the data show that protein‐engineered CR1‐specific chimeric mAbs may negatively regulate disease‐associated B‐lymphocytes and provide therapy for human SLE.
pp. 3301–3311
Are liver NK cells made in the liver?
Natural Killer (NK) cells fulfill key functions in the defense against viruses and tumors and are abundant in the human liver. Since NK cells in the liver display unique characteristics compared with those found in other organs, this begs the question whether hepatic NK cells develop directly from local progenitors residing in the liver. In this issue, Moroso et al. identify and characterize all stages of NK‐cell development (up to the early stem‐cell stage) in the adult human liver. The authors show that these NK‐cell progenitors are not stably resident in the liver, but are continuously recruited from the peripheral circulation. The authors demonstrate that NK‐cell progenitors retrieved from the liver can be induced in vitro to fully mature into functional NK cells. These findings suggest that NK‐cell progenitors from the circulation enter the liver and, from there, may give rise to the population of liver‐specific NK cells.
pp. 3340–3350
IL‐33 augments the effector function of CD8+ T cells
IL‐33 has a well‐established role in type 2 immune responses. In this issue, Yang et al. present a new finding that links IL‐33 and its receptor to CD8+ T cells. The authors show that effector CD8+ T cells express high levels of the IL‐33 receptor ST2. Importantly, the expression of ST2 in CD8+ T cells is dependent on T‐bet, a master Th1 transcription factor, suggesting that ST2 is an integral part of Th1 gene network. In addition, IL‐33 synergizes with TCR and IL‐12 signaling to promote IFN‐γ production. This synergistic effect is partly mediated by Gadd45b, a signaling adaptor. Together, these data establish a novel role for IL‐33 in promoting effector type 1 adaptive immune responses.
pp. 3351–3360