In this issue

Abstract Cover Pictures The cover image schematically depicts the mechanisms proposed by Winkler and colleagues ( pp. 3330–3333) as underlying the extrafollicular activation of rheumatoid factor B cells by chromatin‐immune complexes. The follicular region is shown in orange, the marginal sinus in green, the marginal zone in turquoise, and the red pulp in red. The scheme is based on the data obtained by Shlomchik and colleagues ( pp. 3339–3351) 3339–3351) in their new mouse model of extrafollicular somatic hypermutation, a characteristic of murine lupus. The model importantly uses IgG anti‐chromatin antibodies rather than conventional immune complexes. CrOctin, a new linker for the innate immune system; no men allowed! pp. 3477–3488 Phosphoethanolamine (PE), a component of LPS, helps Gram‐negative bacteria evade cationic antimicrobial peptides by neutralizing the net negative charge of the microbe. However, PE is also recognized by C‐reactive protein (CRP) and serum amyloid P (SAP), pattern recognition receptors (PRR) of the pentraxin superfamily. CRP is known to work together with other plasma proteins during the innate immune response, and Li et al. identify a new PE‐binding pentraxin, CrOctin, from horseshoe crab as one of the members of the CRP „team”. PE‐bound‐CrOctin acts as a linker for CRP and a variety of other PRR, enabling the formation of PRR „interactome” complexes that can activate different immune pathways. Interestingly, the interactions between CrOctin and other PRR are infection‐triggered, which may ensure that the immune system doesn't mistakenly target eukaryotic (self) cells, which also contain PE moieties. However, where CrOctin is involved, it's a girls‐only club: rapid and high expression of CrOctin was stimulated by infection in females, while in males much slower and low/absent expression was observed. Comparing TLR2 ligands. Step 1: how to dilute your lipopeptide pp. 3489–3498 In combination with TLR1 or TLR6, TLR2 is responsible for innate immune recognition of a variety of molecules including lipoteichoic acid (LTA), lipoproteins and lipopeptides. Voss et al. find that the bioactivity of some lipopeptides is affected by the dissolution method and so further investigate dissolution‐dependent differences using fluorescence correlation spectroscopy (FCS). In the absence of a solubilizing agent, i.e. protein (serum/BSA) or detergent, the lipopeptides form large heterogeneous aggregates and are inactive. Aggregation is greatly decreased (and activity increased) following dilution in buffer with serum/BSA, but the differences between lipopeptides differing only in the peptide moiety are still striking. The introduction of an additional dilution step with tert. ‐butyl alcohol further reduces the lipopeptide particle size and results in amazingly similar bioactivities, providing a new solid basis for the analysis of structure‐activity relationships involving lipopeptides. One step back, two steps forward... Treatment with L19mTNF?/melphalan: Reaching an ideal in tumor immunotherapy? pp. 3393–3403 By targeting TNF‐α directly to tumors, the potent antitumor properties of TNF‐α can be exploited without toxic side effects. In mouse (m) tumor models, systemic treatment with TNF‐α fused to the antibody L19 (specific for a fibronectin isoform characteristic of angiogenesis) in combination with the drug melphalan is strikingly effective and generates long‐lasting immunity. Mortara et al. find that effective treatment with L19mTNF‐α/melphalan induces influx of both CD4 + and CD8 + T cells into the tumor and that both populations are indeed required, with CD4 + helpers being necessary to stimulate and maintain efficient CTL. Interestingly, while L19mTNFα induce exclusively IFN‐γ‐producing Th1 cells, melphalan trigger primarily IL‐4‐secreting Th2 cells; as injection of either substance alone fails to induce effective antitumor immunity, this mixed Th1/Th2 CD4 + T cell response seems key to effective treatment. In addition effective L19mTNFα/melphalan treatment reduces the number (but not function!) of CD4 + CD25 + Treg in tumor‐draining LN, while non‐responding animals have significantly higher Treg numbers. Let's hope such targeted tumor‐killing/immune response‐inducing regimens prove similarly effective in humans! Thymocytes, stay on your toes! pp. 3363–3372 While the development of T cells as they pass through the thymus is well‐defined, our understanding of the cells that enable this process, the thymic epithelial cells (TEC) that form the necessary microenvironments for positive and negative selection, is less complete. Gäbler et al. study the development of murine medullary TEC (mTEC), and their findings support the proposed „terminal differentiation model” of mTEC development. In different experimental settings, the authors find evidence that mature CD80 pos mTEC, which express tissue‐restricted (self) antigens promiscuously, develop from immature CD80 neg mTEC. Analysis of BrdU incorporation reveals that a large percentage of immature mTEC are resting or slowly cycling, while a smaller fraction proliferates vigorously. In contrast, turnover of the majority of mature mTEC occurs within 2 to 3 weeks, resulting in a constantly changing environment of self antigens. For thymocytes undergoing selection, there's no time to slack off! Visualizing protective immunity towards Zoster? pp. 3393–3403 Cellular immunity is thought to be crucial for both the control of primary infection with Varicella Zoster Virus (VZV) and the maintenance of latency, with CD4 + T cells playing ‐ at least in terms of frequency ‐ a seemingly dominant role. Although the VZV protein IE63 is expressed during both early viral replication and latency, IE63‐specific CD4 + T cell responses have not been well characterized. In healthy individuals with a history of primary infection, Jones et al. find (using IFN‐γ ELISPOT) that CD4 + T cells dominate the response to IE63 peptides. Truncation analysis of the most commonly recognized peptide reveals a strong epitope restricted by HLA‐DRB1*1501, which enables the generation of (the first VZV‐specific) tetramers and further ex vivo phenotypic analyses. The authors determine that HLA‐DRB1*1501‐restricted IE63‐specific T cells in VZV‐seropositive individuals constitute a mixed central/effector memory population with phenotypic features indicating persistent low‐level (or recurrent) exposure to VZV antigen. This is yet another step towards understanding the players involved in controlling VZV infection and reactivation.