In this issue

Abstract

Cover image

The cover picture features a set of scales representing the “weighing up” of the latest developments and challenges regarding a selected aspect of immunology, as presented in our Viewpoint articles. The focus of the latest Viewpoint series is NK cells, and the cell schematic also presented on the cover depicts the influence/interactions between NK and Treg cells and is taken from the article by Zimmer et al. (pp. 2942–2945). This, and the related article by Andoniou et al. (pp. 2938–2942), discuss the cross-talk between NK cells and adaptive immune cells.

Targeting Sporothrix schenckii surface antigens

pp. 3080–3089

As innocuous as roses may seem, they are in fact one of the many carriers of the fungus Sporothrix schenckii. This fungus is the causative agent of sporotrichosis, a chronic subcutaneous mycosis that occurs worldwide. The immunological mechanisms involved in prevention and control of sporotrichosis remain uncertain. In this issue, Nascimento et al. show for the first time that targeting gp70, a putative adhesion present on the surface of S. schenckii, confers significant protection against infection. Injection of antibody specific against gp70 reduces the number of CFU and increases IFN-γ production by the murine host. Could this be the beginning or the end for sporotrichosis?

Surprising role of AKT beyond β-checkpoint

pp. 3200–3207

The PI3K-AKT pathway mediates diverse biological responses and is crucial for optimal immune responses and early lymphocyte development. Studies with over-expression of activated AKT have implicated this pathway in anti-apoptosis of developing thymocytes and in Treg development. To study the obligatory role of endogenous AKT, in this issue, Xue et al. generate transgenic mice expressing its negative regulator, PTEN in developing T cells after the β-checkpoint. These mice exhibit normal early T-cell development, but the transition from intermediate single positive to double positive (DP) thymocytes is inhibited. This phenotype is similar to that of mice with mutations in the LEF1/TCF-1 transcription factors. Surprisingly, apoptosis of DP cells and subsequent T-cell maturation, including Treg are normal. Indeed, TCR stimulation of DP cells does not lead to AKT phosphorylation. Thus, the PI3K-AKT pathway, is operating in intermediate single positive thymocytes, possibly through the -catenin-LEF1/TCF-1 pathway, but not in later stages of thymocyte development.

Redefining HLA supertype: The HLA-B44 experience

pp. 2993–3003

Extensive variability of HLA alleles and their peptide motifs constitutes a major drawback for peptide-based immunotherapy due to HLA restriction. Grouping similar HLA alleles into HLA supertypes promises to overcome these difficulties by promiscuous peptides binding to several HLA allotypes of the same supertype. In this issue, Hillen et al. scrutinize the definition of the HLA-B44 supertype and its implications on T-cell recognition by analyzing 670 peptides presented by all nine antigens of this supertype revealing unique peptide motifs for each of them. Further evidence for highly individual HLA ligandomes comes from direct molecular comparisons using thousands of MS and MS/MS spectra achieved by isotope labeling and label-free approaches. To investigate the impact on T-cell function the authors test the recognition of immunodominant EBV epitopes in in vivo-primed individuals and demonstrate a lack of promiscuous T-cell responses within the HLA-B44 supertype. These findings question the paradigm of HLA supertypes – at least in case of the HLA-B44 supertype.

No amine oxidases during recovery

pp. 3041–3049

Cessation of blood flow kills the cells in a target organ, typically heart or brain, in a matter of minutes. The only cure for these conditions is rapid restoration of blood supply. Unfortunately, this is not without consequence, as blood-borne leukocytes sweeping the post-ischemic area aggravate tissue destruction. In this issue, Kiss et al. provide evidence that a non-classical adhesion molecule VAP-1 (vascular adhesion protein-1), an amine oxidase expressed on the cell surface, is involved in ischemia-reperfusion injury. The authors show that tissue damage and leukocyte infiltration are attenuated after intestinal ischemia both in the primary (gut) and secondary (lung) target organs in VAP-1 deficient mice. Inhibition of the enzymatic function of VAP-1 by small molecule inhibitors also alleviated the damage. The ecto-enzyme VAP-1 thus appears to recruit leukocytes into post-ischemic tissue, and it may provide a new target for soothing the misguided immune attack.

Getting a grip on IgE

pp. 3167–3177

IgE, a potential runaway-train of the immune system, is known for its strong, unwanted effector functions in allergic diseases, ranging from mild local symptoms to life-threatening systemic reactions. Needless to say, a high systemic IgE titer is hazardous and thus warrants a tight grip on IgE responses. Previously, the limited expression of IgE as a membrane-bound, antigen-receptor-type molecule, finally restricting the recruitment of IgE-producing cells in the immune response was described. In this issue, Achatz-Straussberger et al. present a further mechanism for limiting IgE responses. By means of gene targeting techniques, the authors show that IgE-antibody-secreting cells migrate less efficiently toward the chemokine CXCL12 gradient guiding plasmablasts to plasma cell niches, than IgG1-antibody-secreting cells. Thus, IgE plasmablasts have an intrinsic, lower chance to contribute to the long-lived plasma cell pool and thus to humoral immunological memory than IgG1 plasmablasts.