The immune system evolved to neutralize or kill invading pathogens, while at the same time avoiding reactivity to self, harmless commensal organisms and environmental antigens like allergens. Most often, pathogens are neutralized through the effector mechanisms of innate immunity, such as the activation of complement, and phagocytosis and/or killing by macrophages, neutrophils or eosinophils. These innate responses are reinforced by adaptive immunity, in that humoral immunity facilitates complement activation and phagocytosis by innate immune cells and that particular subsets of T lymphocytes help innate effector cells through release of cytokines. CD4⁺ T helper lymphocytes are divided into broad categories based on the cytokines produced. Th1 lymphocytes produce interferon (IFN)-γ and stimulate the phagocytosis and killing of intracellular bacteria by macrophages. Th17 lymphocytes produce IL-17, which stimulates neutrophils to kill extracellular bacteria and fungi. Th2 lymphocytes produce IL-4, IL-5 and IL-13. IL-5 stimulates the differentiation of eosinophils, which have important roles in killing helminths and other parasites, whereas IL-4 and IL-13 stimulate contraction of smooth muscle and overproduction of mucus, which helps in expulsion of helminths from the gut and lung. The IL-4 (and, to a lesser extent IL-13) produced by Th2 cells also drives the class switching of B cell immunoglobulin production towards immunoglobulin E. Antigen-specific IgE subsequently arms effector cells,, like basophils and mast cells, that express the high affinity IgE receptor (FcRI, Fc receptor I), which rapidly degranulate upon re-encounter with the antigen and help in parasite expulsion or resistance to reinfection [1]. Not surprisingly, therefore, Th2 immune responses are often accompanied by activated eosinophils, basophils, and mast cells, as well as goblet cell hyperplasia and functional changes to the surrounding tissues. These activation loops of innate and adaptive immunity need to be closely regulated. Naturally occurring and induced Treg dampen overt inflammatory reactions to microorganisms, and also suppress immunity to self, by suppressing the activation of innate immune cells, the antigen presenting capacity of dendritic cells and the effector function of Th1, Th2 and Th17 cells.

The study of the functional importance of dendritic cells in various Th2 diseases has been greatly aided by the availability of transgenic models in which dendritic cells can be conditionally depleted or rendered functionally incapable of antigen presentation [9-12]. In one such model, in which cd11cDTR mice were subjected to house dust mite exposure, it was shown that Th2 immunity, as measured by the early production of IL-4 in CD4⁺ T lymphocytes and the development of airway eosinophilia and IL-4, IL-5 and IL-13 production by mediastinal lymph node T cells, failed to develop [8]. Also, it was shown that Th2 immunity and features of Th2-dependent asthma did not develop following inhalation of the harmless protein antigen ovalbumin in the lung when dendritic cells were eliminated [9,10]. This dependence of Th2 immunity on dendritic cells was also seen when mice with chronic airway remodeling (typically seen in asthma of long duration) were exposed to a new allergen [16]. When dendritic cells were depleted during infection with the parasitic helminth Schistosoma mansoni, Th2 immunity failed to develop and responses skewed towards a Th1 dominated response [11]. In a more chronic model of the intestinal parasite Heligmosomoides polygyrus, Th2 effector responses in the gut were severely affected by dendritic cell depletion [12]. Finally, depletion of CD11c^hi dendritic cells in mice exposed to ovalbumin antigen in the Th2 adjuvant alum completely abolished Th2 immunity, as measured by the induction of IgE responses and eosinophilic airway inflammation upon ovalbumin aerosol re-exposure in immunized mice [13]. It was shown that a large part of the adjuvant effects of alum were mediated by the in vivo release of the endogenous danger signal uric acid. When uric acid crystals are mixed with harmless ovalbumin and injected intraperitoneally, this also induced Th2 immunity, and this response was abolished in cd11cDTR mice depleted of dendritic cells [14]. These experiments showed that CD11c^hi dendritic cells are necessary for Th2 immunity. However, it has to be noted that by using the cd11c promoter to deplete dendritic cells, there are also some off target effects. It has been shown that alveolar macrophages and a proportion CD8+ T cells and plasma cells also express CD11c and will, thereby, also be depleted by this treatment [10, 15]. However, adoptive transfer of these affected cell types showed that the effect seen by depleting cells expressing CD11c was due to the depletion of dendritic cells [10].

Having established that dendritic cells are necessary for induction of Th2 immunity, we asked whether they are sufficient. When we transferred as few as 30,000 house dust mite-pulsed lung-derived dendritic cells into the lungs of naïve mice, a Th2 response to house dust mite was induced and eosinophilic airway inflammation developed upon re-exposure of the mice to house dust mite [8]. More precise studies are warranted to define with certainty whether specific subsets of dendritic cells (inflammatory dendritic cells versus subtypes of CD24⁺CD8α⁺CD103⁺ or CD24^-CD11b⁺ conventional dendritic cells) are differentially endowed with potential to induce Th2 immunity. However, this question can be partially, yet indirectly, answered by the fact that Th2 sensitization can be induced by adoptive transfer of GM-CSF cultured bone marrow dendritic cells, most closely resembling mature monocyte-derived CD11b⁺ dendritic cells, but not by Flt3L cultured bone marrow-derived dendritic cells that more resemble the immature, steady-state dendritic cells resident in the lymph nodes and spleen [14,16,18,19]. Lung dendritic cells can be divided into several subsets [17], grossly divided into CD11c⁺ conventional dendritic cells and CD11c^low plasmacytoid dendritic cells. Conventional dendritic cells can be further divided based on expression of either the myeloid marker CD11b or the integrins CD103 (αEβ7) and langerin (CD207) [20]. During inflammation, monocyte-derived inflammatory dendritic cells are also attracted to the site of inflammation [13].

Differentiation of naïve Th cells into Th2 cells requires the upregulation of the transcription factor GATA3 [38] and requires activation of STAT-5 (through IL-2 or TSLP) and STAT-6 transcription factors [39]. GATA3 and STAT-6 activation can be upregulated either through IL-4R signalling or Jagged-Notch signalling [40,41]. Notch-dependent signals have been shown to directly regulate GATA-3 expression and critically control Th cell fate in vivo [40,42,43]. However, it has also been suggested that Notch signals provide survival and proliferative advantages to committed Th cells rather than direct commitment to the Th cell fate [44]. Nonetheless, recently Jagged1, and not Jagged2, expression on dendritic cells has been shown to be critical for IL-4 induction and the promotion of allergic responses. Where exactly the STAT-5 activating signal comes from is less well understood. Dendritic cells have been shown to produce IL-2 and TSLP, but these could also be produced by T cells in an autocrine manner upon T cell activation [45].

One example of this was shown in mice overexpressing GM-CSF, who showed a break of tolerance to the inhaled harmless antigen ovalbumin, and developed a strong Th2 allergic airway inflammation driven by mature dendritic cells [64]. Also, in a mouse model of house dust mite-induced asthma, GM-CSF was shown to be necessary (but not sufficient) for proper Th2 responses [65-68].

Another well-described Th2-inducing cytokine produced by epithelial cells (but also by mast cells and dendritic cells themselves under inflammatory conditions) is TSLP [45,59,69]. Initially, TSLP was found to potently enhance the maturation of CD11c⁺ dendritic cells, and TSLP-primed dendritic cells were shown to promote Th2 differentiation. TSLP was reported to exert its Th2-promoting properties through a dendritic cell-mediated pathway that involved induction of OX40L [59,70-72]. Mice overexpressing TSLP in the lung epithelium had increased asthma features [73], whereas blockade of the TSLP-R inhibited key features of allergic asthma [74]. Besides the effects on dendritic cells, TSLP also influences the function of mast cells and basophils, cell types involved in Th2 responses, by acting as a growth factor [75,76]. In specific helminth infections, like H. polygyrus, N. brasiliensis and S. mansoni, TSLP plays a role in the clearance of worms induced by Th2 immunity [77]. While, TSLP is not necessary for clearing all helminth infections, for Trichuris muris it was shown to be indispensible; this could be because T. muris is less efficient in Th2 induction and more potent than other helminths in triggering Th1 responses [3].

IL-25 (also known as IL-17E) was initially reported as a Th2 cell-derived cytokine, but it can also be produced by basophils [72] and airway epithelial cells in response to allergens and respiratory viruses [78,79]. In mice, overexpression of IL-25 in lung epithelial cells led to allergic inflammation, likely due to the capacity of IL-25 to activate dendritic cells to induce Th2 responses [80]. Injection of neutralizing anti-IL-25 antibodies was able to strongly reduce allergic airway inflammation and airway remodelling [78].

The last group of Th2 instructive cytokines discussed here are the IL-1 family members. Some IL-1 family members are produced as pro-cytokines that require cleavage by caspase-1 through the inflammasome activation to be released [81]. IL-1α and IL-1β both bind to the IL-1 receptor 1 (IL-1RI), which is present on almost all cell types, including structural cells such as airway epithelial cells [82,83]. IL-1β is released from cultured airway epithelial cells following protease allergen exposure and enhances the release of the dendritic cell-attracting chemokine CCL20, and of the dendritic cell maturation cytokines TSLP and GM-CSF [84,85]. IL-1R signalling involves the adaptor molecule MyD88, also found downstream of several TLRs. Interestingly, house dust mite-induced Th2 responses in the lung were found to be strongly reduced in MyD88^-/- mice [86]; however, pathology induced by S. mansoni infection was unaltered [87]. Also, dendritic cells have been shown to express ST2, the receptor for the IL-1 family member IL-33. This cytokine is expressed in airway epithelial cells where it is constitutively stored in nuclei. Its location is unexpected, and how it is released into the extracellular environment remains unclear. It has been postulated, however, that IL-33 might act as an alarmin in case of allergen exposure [88]. Dendritic cells exposed to IL-33 increased their expression of maturation markers, such as CD40 and OX40L and, thereby, became very potent at inducing Th2 responses [89,90]. Both IL-33 and IL-25 have also been shown to induce an allergic phenotype or helminth clearance independent of Th2 lymphocytes [91,92]. In Rag deficient mice, which lack T and B cells, innate lymphoid cells producing IL-5 and IL-13 are induced by IL-25 or IL-33 [93].

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/4/6