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Germinal centers (GCs) represent the main sites for the generation of high-affinity, class-switched antibodies during T cell-dependent antibody responses. To study gene function specifically in GC B cells, we generated C[gamma]1-cre mice in which the expression of Cre recombinase is induced by transcription of the Ig [gamma]1 constant region gene segment (C[gamma]1). In these mice, Cre-mediated recombination at the fas, Ig[beta], IgH, and Rosa26 loci occurred in GC B cells as early as 4 days after immunization with T cell-dependent antigens and involved >85% of GC B cells at the peak of the GC reaction. Less than 2% of Ig[M.sup.+] B cells showed Cre-mediated recombination. These cells carried few lg somatic mutations, expressed germ-line C[gamma]1- and activation-induced cytidine deaminase-specific transcripts and likely include GC B cell founders and/or plasma cell precursors. Cre-mediated recombination involved most IgG1, but also a fraction of IgG3-, IgG2a-, IgG2b-, and IgA-expressing GC and post-GC B cells. This result indicates that a GC B cell can transcribe more than one downstream CH gene before undergoing class switch recombination. The efficient induction of Cre expression in GC B cells makes the C[gamma]1-cre allele a powerful tool for the genetic analysis of these cells, as well as, in combination with a suitable marker for Cre-mediated recombination, the tracking of class-switched memory B and plasma cells in vivo. To expedite the genetic analysis of GC B cells, we have established C[gamma]1-cre [F.sub.1] embryonic stem cells, allowing further rounds of gene targeting and the cloning of compound mutants by tetraploid embryo complementation. class switch recombination | Cre recombinase | memory B | plasma cells

Author(s): Frank L Heppner [1]; Melanie Greter [1, 2]; Denis Marino [1]; Jeppe Falsig [1]; Gennadij Raivich [3]; Nadine Hövelmeyer [4]; Ari Waisman [4]; Thomas Rülicke [5]; Marco Prinz [1, [...]

Various types of T cells with heterogeneous receptors are found in the inflammatory infiltrate in the central nervous system after experimental encephalomyelitis is induced with a T-cell clone L10C1. This clone responds to the myelin basic protein epitope p87-99. It is shown that in vivo tolerization of L10C1 with an analogue of p87-99 reverses established paralysis, reduces inflammatory infiltrates and eliminates the heterogeneous T-cell infiltrate from the brain..

Psoriasis is one of the most common chronic inflammatory skin diseases and at the same time a risk factor for cardiovascular disease. Interleukin‐17A (IL‐17A)–mediated inflammation in psoriasis may lead to vascular dysfunction. This study aimed at investigating whether anti‐inflammatory treatment by tumor necrosis factor (TNF)‐α blockade alters vascular function in psoriasis patients. A total of 11 patients with psoriasis who underwent treatment with either adalimumab (n = 8) or etanercept (n = 3), 10 healthy control individuals and 14 patients with coronary artery disease (CAD) were included in this study. Treatment response was assessed using the Psoriasis Area and Severity Index (PASI) score. Endothelial reactivity and resting endothelium‐dependent vascular tone were assessed by ultrasound measurement of flow‐mediated dilation (FMD) and low‐flow–mediated constriction (l‐FMC), respectively. FMD was slightly impaired in psoriasis patients compared to healthy controls. Anti‐TNF‐α treatment did not significantly change FMD levels. Psoriasis patients showed a trend towards increased baseline vascular activity compared to healthy controls. Anti‐TNF‐α treatment significantly improved l‐FMC in psoriasis patients. Noteworthy, both FMD and l‐FMC in psoriasis patients were comparable to those in patients with CAD; however, an important influence of age differences between the groups or co‐existent classical cardiovascular risk factors on FMD and l‐FMC cannot be ruled out by our small study. The results suggest that anti‐inflammatory treatment with TNF‐α blockade improves vascular function in patients with psoriasis, mainly by altering baseline vascular tone. Further studies will be necessary to establish the potentially protective impact of anti‐inflammatory therapy on vascular function in patients with chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases1–6, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.A subset of inflammatory group 3 innate lymphoid cells, here termed iILC3s, infiltrate the central nervous system and promote neuroinflammation and disease progression in a mouse model of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Medullary thymic epithelial cells (mTECs) are key antigen-presenting cells mediating T cell tolerance to prevent harmful autoimmunity. mTECs both negatively select self-reactive T cells and promote the development of thymic regulatory T cells (tTregs) that mediate peripheral tolerance. The relative importance of these two mechanisms of thymic education to prevent autoimmunity is unclear. We generated a mouse model to specifically target the development and function of mTECs by conditional ablation of the NF-κB–inducing kinase (NIK) in the TEC compartment. In contrast to germline-deficient NIK−/− mice, Foxn1CreNIKfl/fl mice rapidly developed fatal T cell–dependent multiorgan autoimmunity shortly after birth. Thymic transplantation and adoptive transfer experiments demonstrated that autoimmunity arises specifically from the emergence of dysfunctional tTregs. Thus, Treg function, rather than negative selection, enforces the protection of peripheral tissues from autoimmune attack. [ABSTRACT FROM AUTHOR]