Adjuvants are vaccine additives that stimulate the immune system without having any specific antigenic effect of itself. In this study we show that alum adjuvant induces the release of IL-1β from macrophages and dendritic cells and that this is abrogated in cells lacking various NALP3 inflammasome components. The NALP3 inflammasome is also required in vivo for the innate immune response to OVA in alum. The early production of IL-1β and the influx of inflammatory cells into the peritoneal cavity is strongly reduced in NALP3-deficient mice. The activation of adaptive cellular immunity to OVA-alum is initiated by monocytic dendritic cell precursors that induce the expansion of Ag-specific T cells in a NALP3-dependent way. We propose that, in addition to TLR stimulators, agonists of the NALP3 inflammasome should also be considered as vaccine adjuvants.

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...

Tertiary lymphoid organs (TLOs) are organized aggregates of B and T cells formed in postembryonic life in response to chronic immune responses to infectious agents or self-antigens. Although CD11c+ dendritic cells (DCs) are consistently found in regions of TLO, their contribution to TLO organization has not been studied in detail. We found that CD11chi DCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a form of TLO induced in the lungs after influenza virus infection. Elimination of DCs after the virus had been cleared from the lung resulted in iBALT disintegration and reduction in germinal center (GC) reactions, which led to significantly reduced numbers of class-switched plasma cells in the lung and bone marrow and reduction in protective antiviral serum immunoglobulins. Mechanistically, DCs isolated from the lungs of mice with iBALT no longer presented viral antigens to T cells but were a source of lymphotoxin (LT) β and homeostatic chemokines (CXCL-12 and -13 and CCL-19 and -21) known to contribute to TLO organization. Like depletion of DCs, blockade of LTβ receptor signaling after virus clearance led to disintegration of iBALT and GC reactions. Together, our data reveal a previously unappreciated function of lung DCs in iBALT homeostasis and humoral immunity to influenza virus.

Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.