In this issue

The cover image was specifically designed based on an illustration provided by Minguet et al., the authors of Enhanced B-cell activation mediated by TLR4 and BCR crosstalk (EJI 38094, please insert appropriate page number). The authors demonstrate that while simultaneous stimulation of TLR4 and BCR activates B cells in an additive manner, antigen-coupled LPS activates B cells synergistically. The authors proposed this image based on the idea that “science is multidimensional and will never be finished or completely understood”. This image was further enhanced with images taken from various studies published in this issue of the European Journal of Immunology.

DC express several cell-surface, ITIM-harboring immune inhibitory receptors that maintain adequate DC development and/or function; however, little is known about these receptors' immunoregulatory functions in the context of T-cell activation. In this issue, Kasai et al. demonstrate that gp49B, an ITIM-harboring receptor for α_vβ₃ integrin, is expressed on DC, and that gp49B-deficient DC induce enhanced proliferation of, and IL-2 secretion by, antigen-specific CD4⁺ and CD8⁺ T cells in a cell–cell contact manner. The inhibitory role of gp49B at the DC–T cell interface is further demonstrated by the accelerated, lethal acute GVH disease in gp49B-deficient recipients, indicating that gp49B negatively regulates DC function in vitro and in vivo. Previous studies have revealed that gp49B attenuates cytokine and chemokine production by mast cells or macrophages. The present findings highlight the versatility of the inhibitory role of gp49B at the DC–T cell interface in a physiological setting.

B cells are not only precursors for antibody-producing plasma cells but are also APC. In this issue, Shah et al. demonstrate another role for B cells in the maintenance of a population of Treg. Resting B cells are shown to support the survival and expansion of CD4⁺CD25⁺Foxp3⁺ Treg via the production of TGF-β3. Production of TGF-β3 by B cells is in turn down-regulated by TLR signaling or via BCR cross-linking. Reduced TGF-β3 secretion by activated B cells results in decreased survival and expansion of Treg but increased expansion of effector CD4⁺ T cells. Thus, in addition to humoral immune responses, B cells play an important role in balancing T-cell tolerance and immunity, and in preventing autoimmune diseases.

Multiple sclerosis is an inflammatory and autoimmune disease of the central nervous CNS leading to axonal and neuronal loss. In this issue, using the standard experimental model of MS, namely EAE, Fissolo et al. demonstrate increased and altered proteasomal activity in macro- and microglia in the CNS, as well as in lymphoid tissues, in comparison with activity in non-EAE controls. Inhibition of the proteasome with or without inhibition of lysosomal proteases led to amelioration of EAE. This protective effect is most likely due to a reversal of the effects of proteasomal activation, such as increased availability of antigenic peptides, up-regulation of pro-inflammatory molecules and changes in histone de-ubiquitination. These novel findings indicate that understanding proteasomal activity in the CNS may be a key to a better understanding of neurodegenerative diseases.

While intracellular redox is recognized as essential for many metabolic and signaling pathways, less is known about extracellular redox as a modulator of cell function. In this issue, Castellani et al. show that the local shift of extracellular redox toward reduction is a hallmark of the immune response. The thiol content of murine lymphoid organs increases dramatically after antigen injection due to increased thioredoxin production by differentiating B lymphocytes and APC. Thioredoxin promotes extracellular delivery of high levels of non-protein thiols, such as cysteine, which is taken up by T lymphocytes during activation. Thus, a controlled redox regulation forms the basis of correct onset, progress and outcome of the immune response. This study supports the emerging concept that the extracellular redox may control tissue homeostasis by modulating cell proliferation, differentiation or apoptosis, and thereby exerts an influential effect on both health and disease.

Transplantation saves lives and improves the quality of life for thousands of organ-failure patients. Transplantation is, however, not without cost to the patient; non-specific immunosuppression results in complications such as increased risk of infection and cancer. The induction of immunological tolerance for long-term graft survival in the absence of long-term non-specific immunosuppression remains elusive. A promising new development lies in immunotherapy with ex vivo generated or expanded regulatory T cells (Treg). In this issue, Feng and colleagues describe a novel protocol for selection of donor-reactive Foxp3⁺ Treg ex vivo by activating CD4⁺ T cells with GM-CSF/TGF-β-conditioned DC in the presence of IFN-γ. Interestingly, this results in the preferential death of effector cells, suppression of Th17 responses, expansion of naturally occurring Treg and direct conversion of non-Treg precursors. More importantly, these cells prevent transplant rejection without additional manipulation, supporting their further development for the clinical transplantation setting and treatment of autoimmune diseases.