Allergic asthma is characterized by chronic airway inflammation and hyperreactivity and is thought to be mediated by an adaptive T helper-2 (Th2) cell-type immune response. Here, we demonstrate that type 2 pulmonary innate lymphoid cells (ILC2s) significantly contribute to production of the key cytokines IL-5 and IL-13 in experimental asthma. In naive mice, lineage-marker negative ILC2s expressing IL-7Rα, CD25, Sca-1, and T1/ST2(IL-33R) were present in lungs and mediastinal lymph nodes (MedLNs) , IntroductionAllergic asthma is characterized by a predominant eosinophilic airway inflammation, airway hyperreactivity, and a chronic T helper-2 (Th2) cell-type of immune response to various allergens, such as house dust mites (HDMs), molds, or animal dander [1,2]. Available experimental models for asthma indicate that allergenspecific Th2 cells are key players in induction and maintenance of allergic asthma [3]. These cells produce vast amounts of cytokines Correspondence: Dr. Rudi W. Hendriks e-mail: r.hendriks@erasmusmc.nl that induce IgE synthesis (IL-4), recruit eosinophils and mast cells (via IL-5 and IL-9, respectively), and cause smooth muscle hyperreactivity via ).Although adaptive Th2 cells have been identified as important sources of IL-4, , many recent studies emphasize the importance of innate cells in cytokine production, including but not limited to mast cells, eosinophils, and basophils. Next to the canonical NK and lymphoid-tissue inducer (LTi) cells, a growing family of cytokine-producing "helper" innate lymphoid cells (ILCs) has been identified [6]. Interestingly, a lineage-negative ILC population that produces high amounts of IL-5 and IL-13 was identified in fat-associated lymphoid clusters (FALCs) andwww.eji-journal.eu Eur. J. Immunol. 2012. 42: 1106-1116 Immunomodulation 1107 mesenteric lymph nodes [7][8][9]. These cells were named natural helper cells, nuocytes, or multipotent progenitors and, because of their Th2 cytokine production, they have been dubbed type 2 ILCs [6]. ILC2s play a role in defense mechanisms and (re)shaping immune and nonimmune tissues and can be stimulated with IL-25 and IL-33. In a Nocardia brasiliensis infection model, ILC2s were essential and sufficient for clearance of this helminth from the mucosa, even in the absence of the adaptive immune system [7,9]. Recently, various groups demonstrated the presence of ILC2s in the respiratory system of mice and humans [10][11][12]. ILC2 were shown to accumulate in the lungs of mice after infection with influenza virus, via an IL-33 dependent mechanism. These ILC2 induced airway hyperreactivity through IL-13 secretion [10] and also restored airway epithelial integrity and lung function and contributed to airway remodeling by the production of amphiregulin [12]. In addition, ILC2s were found in nasal polyps of patients with chronic rhinitis, a classical Th2 disease [11].IL-25 is a member of the IL-17 cytokine family that is expressed in human and mouse in response to allergens, particles, and helminth infection [13][14][15]. Administ...

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Experimental and clinical observations have highlighted the role of cytotoxic T cells in human tumor control. However, the parameters that control tumor cell sensitivity to T cell attack remain incompletely understood. To identify modulators of tumor cell sensitivity to T cell effector mechanisms, we performed a whole genome haploid screen in HAP1 cells. Selection of tumor cells by exposure to tumor-specific T cells identified components of the interferon-γ (IFN-γ) receptor (IFNGR) signaling pathway, and tumor cell killing by cytotoxic T cells was shown to be in large part mediated by the pro-apoptotic effects of IFN-γ. Notably, we identified schlafen 11 (SLFN11), a known modulator of DNA damage toxicity, as a regulator of tumor cell sensitivity to T cell-secreted IFN-γ. SLFN11 does not influence IFNGR signaling, but couples IFNGR signaling to the induction of the DNA damage response (DDR) in a context dependent fashion. In line with this role of SLFN11, loss of SLFN11 can reduce IFN-γ mediated toxicity. Collectively, our data indicate that SLFN11 can couple IFN-γ exposure of tumor cells to DDR and cellular apoptosis. Future work should reveal the mechanistic basis for the link between IFNGR signaling and DNA damage response, and identify tumor cell types in which SLFN11 contributes to the anti-tumor activity of T cells.