Einleitung Die Tec-Kinase ITK wird hauptsächlich in T-Zellen exprimiert und kann die Transkription von entzündungsfördernden Zytokinen auslösen. Weiterhin verhindert der aktivierte ITK-Signalweg die Apoptose von T-Zellen und induziert Th2-, Th9- und Th17-spezifische Zytokine bei Colitis ulcerosa (CU) [1]. Interessanterweise ist der ITK-Signalweg bei CU-, nicht aber bei Morbus Crohn-Patienten (MC) aktiviert [2] [3]. Weitere Moleküle, die einen Einfluss auf den ITK-Signalweg ausüben können, sind TIM-1 und -3. TIM-Rezeptoren (T cell Immunoglobulin and Mucin domain) werden ebenfalls auf T-Helferzellen exprimiert und können den ITK-Signalweg beeinflussen. TIM1 ist auf der Oberfläche von T-Zellen lokalisiert und wirkt co-stimulierend auf T-Zellen, indem es die T-Zell-Rezeptor-Aktivität erhöht und so vermehrt den ITK-Signalweg stimuliert [4]. Auf der anderen Seite zeigt der Immuncheckpoint Rezeptor TIM3 co-inhibitorische Auswirkungen auf die T-Zell Aktivität [5] [6]. Durch die verstärkte Aktivierung von TIM3 durch Liganden, wie

Einleitung Die Tec-Kinase ITK spielt eine entscheidende Rolle bei der Regulierung von T-Zell-Zytokin-Reaktionen bei Colitis ulcerosa und verhindert die Auflösung der Entzündung. Es wurde gezeigt, dass Itk verschiedene pro-inflammatorische Transkriptionsfaktoren aktivieren und die Zytokine, wie z.B. IL2, IL9 oder IL17A induzieren kann. Zielgerichtetes Inhibieren von ITK führt zu einer verminderten Produktion pro-inflammatorischer Zytokine und verbessert den Krankheitsverlauf in in vivo Modellen [1] [2] [3] [4] [5]. Über die zugrundeliegenden Mechanismen des ITK-Signalwegs ist jedoch noch wenig bekannt. In der Literatur wurden direkte Interaktionen zwischen ITK und TIM (T cell immunoglobulin and mucin domain) Proteinen beschrieben [6] [7] [8]. Wir stellen die Hypothese auf, dass die Inhibition von TIM1 und/oder die Stimulation von TIM3 den Verlauf der Colitis verhindert oder verbessern kann, da TIM1 co-stimulatorische und TIM3 co-inhibitorische Effekte auf T-Zellen hat. Erste Versuche zeigen, dass eine Blockade von TIM1 durch inhibierende Antikörper die Oxazolon induzierte Colitis bei Mäusen verbessern kann.

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r(-/-) and Il3r(+/+) T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.

BACKGROUND:CD56-expressing natural killer (NK) cells as well as invariant NK T (iNKT) cells have been shown to either promote or inhibit allergic immune responses. OBJECTIVE:The aim of the present study was to investigate the impact of these cells in a recently developed humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation. METHODS:Nonobese diabetic-severe combined immunodeficiency γ-chain knockout mice were injected intraperitoneally with human PBMCs or CD56-depleted (CD56neg) PBMCs from highly sensitized donors with birch or grass pollen allergy together with the respective allergen or with NaCl as a control. Three weeks later, the mice were challenged with the allergen rectally and gut inflammation was monitored by video miniendoscopy and by histology. Furthermore, airway inflammation was measured after an additional intranasal allergen challenge. RESULTS:Allergen-specific human IgE in mouse sera, detectable only after coinjection of the respective allergen, was reduced in mice being injected with CD56neg PBMCs compared with in mice receiving nondepleted PBMCs. Consequently, allergen-induced IgE-dependent colitis, airway hyperreactivity, and mucus-producing goblet cells were significantly inhibited in these mice. Interestingly, reconstitution of CD56neg PBMCs with nondepleted CD56+ cells and with CD56+CD3+ iNKT cells restored gut as well as lung inflammation, whereas addition of CD3-depleted CD56+ cells did not. CONCLUSION:These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice is promoted by CD56+CD3+ iNKT cells, which opens new possibilities of therapeutic intervention in allergic diseases.

The pleiotropic function of the cytokine IL-9 is so far described in many inflammation processes and autoimmune diseases. But its role in cancer immunology is rather diverse as it can have a pro-tumorigenic function as well as anti-tumorigenic characteristics. In various disease models of cancer, this cytokine is involved in different signaling pathways triggering the expression of proteins involved in cell growth, migration, and transformation or repressing cells from the adaptive immune system to reject tumor growth. Additionally, there are even therapeutic approaches for IL-9 in cancer development. This review will give an overview of the various roles of IL-9 in different immune organs and cells and provide an insight in the current state of research in the IL-9-dependent cancer area.

Recently, we have developed a humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation in PBMC-engrafted immunodeficient mice. As natural killer (NK) cells have been shown to promote allergen sensitization, type-2 immune responses and airway hyperreactivity, the aim of the present study was to investigate the impact of NK cells in this model. Therefore, NOD-scid-γc-/- mice were injected intraperitoneally with human PBMC or NK cell-depleted PBMC from highly sensitized birch or grass pollen allergic donors together with the respective allergen or with NaCl as control. After an additional allergen boost one week later, mice were challenged with the allergen rectally on day 21 and gut inflammation was monitored by video mini-endoscopy evaluating translucency, granularity, fibrin production, vascularity, and stool. Then, mice were further challenged intranasally on two subsequent days and airway inflammation was measured by invasive body plethysmography and by histology. Allergen-specific human IgE in mouse sera, if detectable after co-injection of the respective allergen, was reduced in mice being injected with NK cell-depleted PBMC compared to mice which received non-depleted PBMC. Additionally, allergen-induced IgE-dependent colitis, airway hyperreactivity and mucus-producing goblet cells were significantly inhibited in these mice. Importantly, infiltration of the colon and lung with human CD45+ cells was similar in all groups. These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice can be diminished by depletion of NK cells prior to PBMC transfer, which may be of great interest for therapeutic intervention of allergic diseases.

Inflammatory bowel diseases (IBD) are chronic, relapsing and aggravating disorders in which the homeostasis in the gastrointestinal tract has been altered by aberrant immune responses towards environmental and microbial assaults in genetically predisposed individuals. The contribution of type I interferon signaling (i.e. STAT1:STAT2:IRF9) in the pathogenesis of IBD is controversial since conflicting results indicating either a protective or a supporting role during inflammation exist. We investigated the role of STAT2 in models of IBD and intestinal mucosal healing.